Guanidino compounds

ABSTRACT

A variety of small, guanidino group-containing molecules capable of acting as MC4-R agonists are provided. The compounds have various structures provided herein. The compounds are useful in treating MC4-R mediated diseases and may be formulated into pharmaceutical formulations and compositions.

FIELD OF THE INVENTION

This invention relates to melanocortin-4 receptor (MC4-R) agonists andmethods of their preparation. The invention also relates to methods oftreating melanocortin-4 receptor-mediated diseases, such as obesity ordiabetes, by activating the melanocortin-4 receptor with compoundsprovided herein.

BACKGROUND OF THE INVENTION

Melanocortins are peptide products resulting from post-translationalprocessing of pro-opiomelanocortin and are known to have a broad arrayof physiological activities. The natural melanocortins include thedifferent types of melanocyte stimulating hormone (α-MSH, β-MSH, γ-MSH)and ACTH. Of these, α-MSH and ACTH are considered to be the mainendogenous melanocortins.

The melanocortins mediate their effects through melanocortin receptors(MC-Rs), a subfamily of G-protein coupled receptors. There are at leastfive different receptor subtypes (MC1-R to MC5-R). MC1-R mediatespigmentation of the hair and skin. MC2-R mediates the effects of ACTH onsteroidogenesis in the adrenal gland. MC3-R and MC4-R are predominantlyexpressed in the brain. MC5-R is considered to have a role in theexocrine gland system.

The melanocortin-4 receptor (MC4-R) is a seven-transmembrane receptor.MC4-R may participate in modulating the flow of visual and sensoryinformation, coordinate aspects of somatomotor control, and/orparticipate in the modulation of autonomic outflow to the heart. K. G.Mountjoy et al., Science, 257:1248-125 (1992). Significantly,inactivation of this receptor by gene targeting has resulted in micethat develop a maturity onset obesity syndrome associated withhyperphagia, hyperinsulinemia, and hyperglycemia. D. Husznar et al.,Cell, 88(1): 131-41 (1997). MC4-R has also been implicated in otherdisease states including erectile disorders, cardiovascular disorders,neuronal injuries or disorders, inflammation, fever, cognitivedisorders, and sexual behavior disorders. M. E. Hadley and C.Haskell-Luevano, The proopiomelanocortin system, Ann. N.Y. Acad. Sci.,885:1 (1999).

Furthermore, observations in connection with endogenous MCx-Rantagonists indicate that MC4-R is implicated in endogenous energyregulation. For example, an agouti protein is normally expressed in theskin and is an antagonist of the cutaneous MC receptor involved inpigmentation, MC1-R. M. M. Ollmann et al., Science, 278:135-138 (1997).However, overexpression of agouti protein in mice leads to a yellow coatcolor due to antagonism of MC1-R and increased food intake and bodyweight due to antagonism of MC4-R. L. L. Kiefer et al., Biochemistry,36: 2084-2090 (1997); D. S. Lu et al., Nature, 371:799-802 (1994).Agouti related protein (AGRP), an agouti protein homologue, antagonizesMC4-R but not MC1-R. T. M. Fong et al., Biochem. Biophys. Res. Commun.237:629-631 (1997). Administration of AGRP in mice increases food intakeand causes obesity but does not alter pigmentation. M. Rossi et al.,Endocrinology, 139:4428-4431 (1998). Together, this research indicatesthat MC4-R participates in energy regulation, and therefore, identifiesthis receptor as a target for a rational drug design for the treatmentof obesity.

In connection with MC4-R and its uncovered role in the etiology ofobesity and food intake, the prior art includes reports of compounds andcompositions that act as agonists or antagonists of MC4-R. As examples,U.S. Pat. No. 6,060,589 describes polypeptides that are capable ofmodulating signaling activity of melanocortin receptors. Also, U.S. Pat.Nos. 6,054,556 and 5,731,408 describe families of agonists andantagonists for MC4-R receptors that are lactam heptapeptides having acyclic structure. WO 01/10842 discloses MC4-R binding compounds having amultitude of structures and methods of using such compounds to treatMC4-R associated disorders. Some of the compounds described includeamidino- and guanidino-containing arenes and heteroarenes.

Various other classes of compounds have been disclosed as having MC4-Ragonist activity. For example, WO 01/70708 and WO 00/74679 discloseMC4-R agonists that are piperidine compounds and derivatives, while WO01/70337 and WO 99/64002 disclose MC-R agonists that are spiropiperidinederivatives. Other known melanocortin receptor agonists include aromaticamine compounds containing amino acid residues, particularly tryptophanresidues, as disclosed in WO 01/55106. Similar agonists are disclosed inWO 01/055107 which comprise aromatic amine compounds containing tertiaryamide or tertiary amine groups. Finally, WO 01/055109 disclosesmelanocortin receptor agonists comprising aromatic amines which aregenerally bisamides separated by a nitrogen-containing alkyl linker.

Guanidine-containing compounds having a variety of biological activitiesare also known in the prior art. For example, U.S. Pat. No. 4,732,916issued to Satoh et al. discloses guanidine compounds useful as antiulceragents; U.S. Pat. No. 4,874,864, U.S. Pat. No. 4,949,891, and U.S. Pat.No. 4,948,901 issued to Schnur et al. and EP 0343 894 disclose guanidinocompounds useful as protease inhibitors and as anti-plasmin andanti-thrombin agents; and U.S. Pat. No. 5,352,704 issued to Okuyama etal. discloses a guanidino compound useful as an antiviral agent.Guanidine-containing compounds are also disclosed in other references.For example, U.S. Pat. No. 6,030,985 issued to Gentile et al. disclosesguanidine compounds useful for treating and preventing conditions inwhich inhibition of nitric oxide synthetase is beneficial such asstroke, schizophrenia, anxiety, and pain. U.S. Pat. No. 5,952,381 issuedto Chen et al. discloses certain guanidine compounds for use inselectively inhibiting or antagonizing α_(v)β₃ integrins.

Various 5-, 6-, and 7-membered fully saturated1-azacarbocyclic-2-ylidene derivatives of guanidine are disclosed ashaving anti-secretory and hypoglycemic activities by U.S. Pat. No.4,211,867 issued to Rasmussen. Such compounds are also taught as usefulfor the treatment of cardiovascular disease. Other guanidine derivativesare disclosed by U.S. Pat. No. 5,885,985 issued to Macdonald et al. asuseful in therapy to treat inflammation.

Nevertheless, there remains a need for potent and specific agonists ofMC4-R that are low molecular weight small molecules. Methods of treatinga melanocortin-4 receptor mediated disease, such as obesity, with suchnon-peptide drugs, are also particularly desirable.

SUMMARY OF THE INVENTION

The instant invention provides potent and specific agonists of MC4-Rthat are low molecular weight small molecules. Thus, there has beenprovided, in accordance with one aspect of the invention, compounds offormula A¹-A²-A³-A⁴:

-   -   wherein    -   A¹ is a group of formula IIA or IIB;    -   R^(1′) is selected from the group consisting of H, and        substituted and unsubstituted alkyl, alkenyl, alkynyl,        cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl,        heteroarylalkyl, and cycloalkylalkyl groups;    -   R^(2′) is selected from the group consisting of substituted and        unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, and        cycloalkylalkyl groups; or    -   R^(1′) and R^(2′), together with the nitrogen to which they are        bound, form a substituted or unsubstituted heterocyclyl or        heteroaryl group;    -   R^(3′) is selected from the group consisting of substituted and        unsubstituted aryl, alkyl, alkenyl, alkynyl, cycloalkyl,        heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl,        heteroarylalkyl, and cycloalkylalkyl groups;    -   R^(4′) is selected from the group consisting of H, and        substituted and unsubstituted alkyl, alkenyl, alkynyl,        cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl,        heteroaryl, heterocyclyl, arylalkyl, and heteroarylalkyl groups;    -   A² is selected from the group consisting of substituted and        unsubstituted aryl groups and substituted and unsubstituted        heteroaryl groups;    -   A³ is a covalent bond such that A² is directly bonded to A⁴, or        A³ is a linking group selected from the group consisting of O,        S, —NR^(a), —C(═O)—, —C(═O)O—, —NR^(a)C(═O)—, —SO₂NR^(a)—,        —C(═S)—, —C(═O)S—, —P(═O)R^(b)—, —SO₂—, and —S(═O)—, wherein if        A³ is a linking group, then it is bonded to A² and A⁴ in a        configuration selected from the group consisting of A²-O-A⁴,        A²-S-A⁴, A²-NR^(a)-A⁴, A²-C(═O)-A⁴, A²-C(═O)O-A⁴, A⁴-C(═O)O-A²,        A²-NR^(a)C(═O)-A⁴, A⁴-NR^(a)C(═O)-A², A²-SO₂NR^(a)-A⁴,        A⁴-SO₂NR^(a)-A², A²-C(═S)-A⁴, A²-(C═O)S-A⁴, A⁴-(C═O)S-A²,        A²-(P═O)R^(b)-A⁴, A²-SO₂-A⁴, and A²-S(═O)-A⁴ provided that if A³        is a linking group with the configuration A⁴-NR^(a)C(═O)-A²,        then A² is not a substituted or unsubstituted phenyl group and        is not a substituted or unsubstituted 6-membered N-containing        heteroaryl group;    -   A⁴ is selected from the group consisting of substituted and        unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl,        heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl,        alkenyl, alkynyl, and alkyl groups;    -   R^(a) is selected from the group consisting of H, and        substituted and unsubstituted arylalkyl, heteroarylalkyl, aryl,        heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl,        cycloalkylalkyl, alkenyl, alkynyl, and alkyl groups; and    -   R^(b) is selected from the group consisting of substituted and        unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl,        heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl,        alkenyl, alkynyl, and alkyl groups.

Compounds provided by the invention further include prodrugs of thecompound of A¹-A²-A³-A⁴, pharmaceutically acceptable salts thereof,stereoisomers thereof, tautomers thereof, hydrates thereof, hydridesthereof, or solvates thereof.

The invention provides further compounds of formula A¹-A²-A³-A⁴ in whichA² is selected from the group consisting of substituted andunsubstituted phenyl groups and substituted and unsubstituted pyridylgroups.

The invention further provides compounds in which A³ is a linking groupbonded to A² and A⁴ in a configuration selected from the groupconsisting of A²-NR^(a)-A⁴, A²-C(═O)-A⁴, A²-C(═O)O-A⁴, A⁴-C(═O)O-A²,A²-NHC(═O)-A⁴, A²-SO₂NH-A⁴, and A²-SO₂-A⁴.

The invention provides further compounds of formula A¹-A²-A³-A⁴ in whichR^(3′) is selected from the group consisting of substituted andunsubstituted cycloalkyl, polycyclic cycloalkyl, alkenyl, alkyl, andaryl groups. In other embodiments of compounds of formula A¹-A²-A³-A⁴,R³ is selected from the group consisting of substituted andunsubstituted cyclohexyl, 2-alkylcyclohexyl, 2,2-dialkylcyclohexyl,2,3-dialkylcyclohexyl, 2,4-dialkylcyclohexyl, 2,5-dialkylcyclohexyl,2,6-dialkylcyclohexyl, 3,4-dialkylcyclohexyl, 3-alkylcyclohexyl,4-alkylcyclohexyl, 3,3,5-trialkylcyclohexyl, cyclohexylmethyl,2-aminocyclohexyl, 3-aminocyclohexyl, 4-aminocyclohexyl,2,3-diaminocyclohexyl, 2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl,2,5-diaminocyclohexyl, 2,6-diaminocyclohexyl, 2,2-diaminocyclohexyl,2-alkoxycyclohexyl, 3-alkoxycyclohexyl, 4-alkoxycyclohexyl,2,3-dialkoxycyclohexyl, 2,4-dialkoxycyclohexyl, 3,4-dialkoxycyclohexyl,2,5-dialkoxycyclohexyl, 2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl,2-alkylthiocyclohexyl, 3-alkylthiocyclohexyl, 4-alkylthiocyclohexyl,2,3-dialkylthiocyclohexyl, 2,4-dialkylthiocyclohexyl,3,4-dialkylthiocyclohexyl, 2,5-dialkylthiocyclohexyl,2,6-dialkylthiocyclohexyl, 2,2-dialkylthiocyclohexyl, cyclopentyl,cycloheptyl, cyclohexenyl, isopropyl, n-butyl, cyclooctyl,2-arylcyclohexyl, 2-phenylcyclohexyl, 2-arylalkylcyclohexyl,2-benzylcyclohexyl, 4-phenylcyclohexyl, adamantyl, isocamphenyl,carenyl, 7,7-dialkylnorbornyl, bornyl, norbornyl, and decalinyl groups.In still other embodiments of compounds of formula A¹-A²-A³-A⁴, R³ isselected from the group consisting of substituted and unsubstitutedcyclohexyl, 2-methylcyclohexyl, 2,2-dimethylcyclohexyl,2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl,2,6-dimethylcyclohexyl, 3,4-dimethylcyclohexyl, 3-methylcyclohexyl,4-methylcyclohexyl, cyclohexenyl, 3,3,5-trimethylcyclohexyl,4-t-butylcyclohexyl, cyclohexylmethyl, isopinocampheyl,7,7-dimethylnorbornyl, 4-isopropylcyclohexyl, and 3-methylcycloheptylgroups.

The invention provides further compounds of formula A¹-A²-A³-A⁴ in whichR^(1′) is H and R^(2′) is selected from the group consisting ofsubstituted and unsubstituted alkyl, arylalkyl, and heteroarylalkylgroups. In still other embodiments of compounds of formula A¹-A²-A³-A⁴,R^(1′) is H and R^(2′) is selected from the group consisting ofsubstituted and unsubstituted dialkylaminoethyl, 4-ethylbenzyl,3-chlorobenzyl, 2,4-dichlorobenzyl, 3-methylbenzyl, benzyl,4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl, and thiophene groups.In still other embodiments of compounds of formula A¹-A²-A³-A⁴, R^(1′)and R^(2′) may be the same or different and are each independentlyselected from the group consisting of substituted and unsubstitutedalkyl, arylalkyl, and heteroarylalkyl groups. In still other embodimentsof compounds of formula A¹-A²-A³-A⁴, R^(1′) and R^(2′) may be the sameor different and are each independently selected from the groupconsisting of substituted and unsubstituted dialkylaminoethyl,4-ethylbenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl, 3-methylbenzyl,benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl, and thiophenegroups.

In still other embodiments of compounds of formula A¹-A²-A³-A⁴, R^(1′)and R^(2′), together with the nitrogen to which they are bound, form asubstituted or unsubstituted heterocyclyl group. In still otherembodiments of compounds of formula A¹-A²-A³-A⁴, R^(1′) and R^(2′),together with the nitrogen to which they are bound, form a substitutedor unsubstituted saturated heterocyclyl group comprising at least oneheteroatom selected from the group consisting of O, S, and N, inaddition to the nitrogen atom to which R^(1′) and R^(2′) are bound. Instill other embodiments of compounds of formula A¹-A²-A³-A⁴, R^(1′) andR^(2′) together with the nitrogen to which they are bound, form asubstituted or unsubstituted piperazino, morpholino, pyrrolidino,piperidino, homopiperazino, or azepino group. In still other embodimentsof compounds of formula A¹-A²-A³-A⁴, R^(1′) and R^(2′), together withthe nitrogen to which they are bound, form a piperazino group optionallysubstituted by one or two methyl groups.

The invention provides further compounds of formula A¹-A²-A³-A⁴ in whichR^(a) is H.

The invention provides further compounds of formula A¹-A²-A³-A⁴ in whichA³ is a covalent bond so that A² is directly bonded to A⁴.

The invention provides further compounds of formula A¹-A²-A³-A⁴ in whichA⁴ is a 2,4-disubstituted phenylethyl group or an indolylethyl group. Instill other embodiments of compounds of formula A¹-A²-A³-A⁴, A⁴ isselected from the group consisting of 2,4-dihalophenylethyl, and2,4-dialkylphenylethyl groups. In still other embodiments of compoundsof formula A¹-A²-A³-A⁴, A⁴ is selected from the group consisting ofphenylethyl, 2,4-dichlorophenylethyl, 4-methoxyphenylethyl,4-bromophenylethyl, 4-methylphenylethyl, 4-chlorophenylethyl,4-ethylphenylethyl, cyclohexenylethyl, 2-methoxyphenylethyl,2-chlorophenylethyl, 2-fluorophenylethyl, 3-methoxyphenylethyl,3-fluorophenylethyl, thienylethyl, indolylethyl, 4-hydroxyphenylethyl,3,4-dimethoxyphenylethyl, 2-chloro-4-iodophenylethyl,2-fluoro-4-methylphenylethyl, 2-fluoro-4-bromophenylethyl,2-fluoro-4-methoxyphenylethyl, 2-trifluoromethyl-4-fluorophenylethyl,2,4-difluorophenylethyl, 2,4-dimethylphenylethyl, or2,4-dimethoxyphenylethyl groups.

In accordance with another aspect of the invention, there has beenprovided, a compound of formula I:

-   -   wherein    -   Q, W, X, Y, and Z are independently selected from the group        consisting of carbon atoms and nitrogen atoms;    -   R¹, R², R³, R⁴, and R⁵ may be the same or different, and are        each independently selected from the group consisting of H, Cl,        I, F, Br, OH, NH₂, CN, NO₂, and substituted and unsubstituted        aryl, alkoxy, amino, alkyl, alkenyl, alkynyl, alkylamino,        dialkylamino, cycloalkyl, heterocyclylamino, heteroarylamino,        aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,        cycloalkylaminocarbonyl, arylaminocarbonyl,        heterocyclylaminocarbonyl, heteroarylaminocarbonyl groups, and        groups of formula IIA or IIB;        wherein R¹ may be absent if W is a nitrogen atom;    -   wherein R² may be absent if X is a nitrogen atom;    -   wherein R³ may be absent if Z is a nitrogen atom;    -   wherein R⁴ may be absent if Y is a nitrogen atom;    -   wherein R⁵ may be absent if Q is a nitrogen atom;    -   wherein one of R¹, R², R³, R⁴, or R⁵ is a group having the        formula IIA or IIB;    -   R^(1′) is selected from the group consisting of H, and        substituted and unsubstituted alkyl, alkenyl, alkynyl,        cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl,        heteroarylalkyl, and cycloalkylalkyl groups;    -   R^(2′) is selected from the group consisting of substituted and        unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl,        heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, and        cycloalkylalkyl groups; or    -   R^(1′) and R^(2′), together with the nitrogen to which they are        bound, form a substituted or unsubstituted heterocyclyl or        heteroaryl group;    -   R^(3′) is selected from the group consisting of substituted and        unsubstituted aryl, alkyl, alkenyl, alkynyl, cycloalkyl,        heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl,        heteroarylalkyl, and cycloalkylalkyl groups;    -   R^(4′) is selected from the group consisting of H, and        substituted and unsubstituted alkyl, alkenyl, alkynyl,        cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl,        heteroaryl, heterocyclyl, arylalkyl, and heteroarylalkyl groups;

-   R⁶ is a group of formula IIIA, IIIB, IIIC, IIID, or IIIE;    -   m is an integer selected from 0, 1, or 2;    -   n is an integer selected from 0, 1, or 2;    -   R⁷, R⁸, R⁹, and R¹⁰ may be the same or different and are        independently selected from the group consisting of H, Cl, I, F,        Br, OH, NH₂, CN, NO₂, and substituted and unsubstituted alkoxy,        amino, alkyl, aryl, alkenyl, alkynyl, alkylamino, dialkylamino,        cycloalkyl, heterocyclylamino, heteroarylamino, aminocarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl,        cycloalkylaminocarbonyl, arylaminocarbonyl,        heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups;    -   R⁷ and R⁸ may join together with the carbon atoms to which they        are attached to form a substituted or unsubstituted 5 or 6        membered ring;    -   R¹¹ is selected from the group consisting of H, and substituted        and unsubstituted alkyl groups;    -   R¹², R¹³, R¹⁴, and R¹⁵ may be the same or different and are each        independently selected from the group consisting of H, Cl, I, F,        Br, OH, NH₂, CN, NO₂, and substituted and unsubstituted alkoxy,        amino, alkyl, aryl, alkenyl, alkynyl, alkylamino, dialkylamino,        cycloalkyl, heterocyclylamino, heteroarylamino, aminocarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl,        cycloalkylaminocarbonyl, arylaminocarbonyl,        heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups;    -   R¹² and R¹⁴ may represent a second bond between the carbon        bonded to R¹² and the carbon bonded to R¹⁴ such that the bond        between the carbon bonded to R¹² and the carbon bonded to R¹⁴ is        a double bond; and    -   R¹⁶ is selected from the group consisting of H, and substituted        and unsubstituted alkyl groups;    -   R¹¹ and R¹⁶ may represent a second bond between the carbon        bonded to R¹⁶ and the nitrogen bonded to R¹¹ such that the bond        between the carbon bonded to R¹⁶ and the nitrogen bonded to R¹¹        is a double bond;    -   R¹⁷ is selected from the group consisting of H, and substituted        and unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl,        heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl,        alkenyl, alkynyl, and alkyl groups;    -   R¹⁸ is selected from the group consisting of H, and substituted        and unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl,        heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl,        alkenyl, alkynyl, and alkyl groups; and    -   R¹⁹ is selected from the group consisting of substituted and        unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl,        heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl,        alkenyl, alkynyl, and alkyl groups.

Compounds provided by the invention further include prodrugs of thecompound of formula I, pharmaceutically acceptable salts thereof,stereoisomers thereof, tautomers thereof, hydrates thereof, hydridesthereof, or solvates thereof.

In one embodiment R⁶ has the formula IIIA. In some embodiments where R⁶has the formula IIIA, m is 0 and n is 2. In other embodiments where R⁶has the formula IIIA, m is 1 and n is 1. In still other embodimentswhere R⁶ has the formula IIIA, m is 0 and n is 1. In yet otherembodiments where R⁶ has the formula IIIA, m is 2 and n is 1.

In another embodiment R⁶ has the formula IIIB. In some embodiments whereR⁶ has the formula IIIB, R¹¹ and R¹⁶ represent a second bond between thecarbon bonded to R¹⁶ and the nitrogen bonded to R¹¹ such that the bondbetween the carbon bonded to R¹⁶ and the nitrogen bonded to R¹¹ is adouble bond. In other embodiments where R⁶ has the formula IIIB, R¹¹ isH or a substituted or unsubstituted alkyl group and R¹⁶ is H.

In other embodiments in which R⁶ is a group of formula IIIA or IIIB, atleast one of R⁸ or R⁹ is selected from the group consisting of Br, Cl,F, I substituted and unsubstituted alkyl groups, and substituted andunsubstituted alkoxy groups.

The invention provides further compounds of formula I in which R⁶ hasthe formula IIIC.

The invention provides further compounds of formula I in which R⁶ hasthe formula IIID. In other embodiments, R⁶ has the formula IIIE. In someembodiments in which R⁶ has the formula IIID or IIIE, R¹⁸ is H. In otherembodiments in which R⁶ has the formula IIID, R¹⁹ is a substitutedarylalkyl group, and the alkyl group of the R¹⁹ arylalkyl group issubstituted with an amino or acetamido group.

In other embodiments in which R⁶ is a group of formula IIIC, IIID orIIIE, R¹⁷ or R¹⁹ is selected from the group consisting of substitutedand unsubstituted arylalkyl groups, and substituted and unsubstitutedheteroarylalkyl groups. In other embodiments in which R⁶ is a group offormula IIIC, IIID, or IIIE, R¹⁷ or R¹⁹ is a substituted orunsubstituted phenylalkyl group or a substituted or unsubstitutedindolylalkyl group. In still other embodiments in which R⁶ is a group offormula IIIC, IIID, or IIIE, R¹⁷ or R¹⁹ is a 2,4-disubstitutedphenylethyl group or an indolylethyl group. In still other embodimentsin which R⁶ is a group of formula IIIC, IIID, or IIIE, R¹⁷ or R¹⁹ isselected from the group consisting of 2,4-dihalophenylethyl, and2,4-dialkylphenylethyl groups. In still other embodiments in which R⁶ isa group of formula IIIC, IIID, or IIIE, R¹⁷ or R¹⁹ is selected from thegroup consisting of phenylethyl, 2,4-dichlorophenylethyl,4-methoxyphenylethyl, 4-bromophenylethyl, 4-methylphenylethyl,4-chlorophenylethyl, 4-ethylphenylethyl, cyclohexenylethyl,2-methoxyphenylethyl, 2-chlorophenylethyl, 2-fluorophenylethyl,3-methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, indolylethyl,4-hydroxyphenylethyl, 3,4-dimethoxyphenylethyl,2-chloro-4-iodophenylethyl, 2-fluoro-4-methylphenylethyl,2-fluoro-4-bromophenylethyl, 2-fluoro-4-methoxyphenylethyl,2-trifluoromethyl-4-fluorophenylethyl, 2,4-difluorophenylethyl,2,4-dimethylphenylethyl, or 2,4-dimethoxyphenylethyl groups. In someembodiments such as those described above in which R¹⁷ or R¹⁹ is asubstituted or unsubstituted arylalkyl group such as a substituted orunsubstituted arylethyl group or more specifically a substitutedphenylethyl group, the alkyl or ethyl group of the substituted orunsubstituted arylalkyl group is further substituted with a group suchas an amino group; an alkylamino group such as a methylamino group; ahydroxyalkyl group such as a hydroxymethyl group; an —N(H)C(═O)-alkylgroup such as a —N(H)C(═O)—CH₃ group; an —N(H)C(═O)—O-alkyl group suchas a —N(H)C(═O)—O—C(CH₃)₃ group; or an —N(H)C(═O)—O-arylalkyl group suchas a —N(H)C(═O)—O-benzyl group; an —N(H)C(═O)-heterocyclyl group such asa —N(H)C(═O)-(1,2,3,4-tetrahydroisoquinoline) group; or anarylalkoxyalkyl group, such as a phenylmethoxymethyl group, a3-bromophenylmethoxymethyl group, a 4-methylphenylmethoxymethyl group, a4-fluorophenylmethoxymethyl group, a2-fluoro-4-chlorophenylmethoxymethyl group, and the like.

In other embodiments having any of the features described above, Q is acarbon atom and R⁵ is a group having the formula IIA or IIB.

In some embodiments, Q, W, X, Y, and Z are all carbon atoms whereas inother embodiments one of Q, W, X, Y, or Z is a nitrogen atom such thatthe ring containing Q, W, X, Y, and Z is a pyridine ring.

In other embodiments having any of the features described above, R^(4′)is H.

Other embodiments are provided which have any of the features describedabove in which R^(3′) is selected from the group consisting ofsubstituted and unsubstituted cycloalkyl, polycyclic cycloalkyl,alkenyl, alkyl, and aryl groups. In still other embodiments, R³ isselected from the group consisting of substituted and unsubstitutedcyclohexyl, 2-alkylcyclohexyl, 2,2-dialkylcyclohexyl,2,3-dialkylcyclohexyl, 2,4-dialkylcyclohexyl, 2,5-dialkylcyclohexyl,2,6-dialkylcyclohexyl, 3,4-dialkylcyclohexyl, 3-alkylcyclohexyl,4-alkylcyclohexyl, 3,3,5-trialkylcyclohexyl, cyclohexylmethyl,2-aminocyclohexyl, 3-aminocyclohexyl, 4-aminocyclohexyl,2,3-diaminocyclohexyl, 2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl,2,5-diaminocyclohexyl, 2,6-diaminocyclohexyl, 2,2-diaminocyclohexyl,2-alkoxycyclohexyl, 3-alkoxycyclohexyl, 4-alkoxycyclohexyl,2,3-dialkoxycyclohexyl, 2,4-dialkoxycyclohexyl, 3,4-dialkoxycyclohexyl,2,5-dialkoxycyclohexyl, 2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl,2-alkylthiocyclohexyl, 3-alkylthiocyclohexyl, 4-alkylthiocyclohexyl,2,3-dialkylthiocyclohexyl, 2,4-dialkylthiocyclohexyl,3,4-dialkylthiocyclohexyl, 2,5-dialkylthiocyclohexyl,2,6-dialkylthiocyclohexyl, 2,2-dialkylthiocyclohexyl, cyclopentyl,cycloheptyl, cyclohexenyl, isopropyl, n-butyl, cyclooctyl,2-arylcyclohexyl, 2-phenylcyclohexyl, 2-arylalkylcyclohexyl,2-benzylcyclohexyl, 4-phenylcyclohexyl, adamantyl, isocamphenyl,carenyl, 7,7-dialkylnorbornyl, bornyl, norbornyl, and decalinyl groups.In still other embodiments, R^(3′) is selected from the group consistingof substituted and unsubstituted cyclohexyl, 2-methylcyclohexyl,2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl,2,5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl, 3,4-dimethylcyclohexyl,3-methylcyclohexyl, 4-methylcyclohexyl, cyclohexenyl,3,3,5-trimethylcyclohexyl, 4-t-butylcyclohexyl, cyclohexylmethyl,isopinocampheyl, 7,7-dimethylnorbornyl, 4-isopropylcyclohexyl, and3-methylcycloheptyl groups. In some embodiments, R³ is a substitutedcyclohexyl group such as a trifluoromethyl substituted cyclohexyl groupsuch as a 4-trifluoromethylcyclohexyl group.

Other embodiments are provided which have any of the features describedabove in which R^(1′) is H and R^(2′) is selected from the groupconsisting of substituted and unsubstituted alkyl, arylalkyl, andheteroarylalkyl groups. In still other embodiments, R^(1′) is H andR^(2′) is selected from the group consisting of substituted andunsubstituted dialkylaminoethyl, 4-ethylbenzyl, 3-chlorobenzyl,2,4-dichlorobenzyl, 3-methylbenzyl, benzyl, 4-fluorobenzyl,3-methoxybenzyl, 2-chlorobenzyl, and thiophene groups. In still furtherembodiments, R^(1′) and R^(2′) may be the same or different and are eachindependently selected from the group consisting of substituted andunsubstituted alkyl, arylalkyl, and heteroarylalkyl groups. In yet otherembodiments, R^(1′) and R^(2′) may be the same or different and are eachindependently selected from the group consisting of substituted andunsubstituted dialkylaminoethyl, 4-ethylbenzyl, 3-chlorobenzyl,2,4-dichlorobenzyl, 3-methylbenzyl, benzyl, 4-fluorobenzyl,3-methoxybenzyl, 2-chlorobenzyl, and thiophene groups. In still otherembodiments, R^(1′) and R^(2′), together with the nitrogen to which theyare bound, form a substituted or unsubstituted heterocyclyl group. Inother embodiments, R^(1′) and R^(2′), together with the nitrogen towhich they are bound, form a substituted or unsubstituted saturatedheterocyclyl group comprising at least one heteroatom selected from thegroup consisting of O, S, and N, in addition to the nitrogen atom towhich R^(1′) and R^(2′) are bound. In yet other embodiments, R^(1′) andR^(2′), together with the nitrogen to which they are bound, form asubstituted or unsubstituted piperazino, morpholino, pyrrolidino,piperidino, homopiperazino, or azepino group. In still furtherembodiments, R^(1′) and R^(2′), together with the nitrogen to which theyare bound, form a piperazino group optionally substituted by one or twomethyl groups.

In some embodiments, if R¹⁷ is H or an unsubstituted alkyl group, thenR^(1′) and R^(2′) join together, with the nitrogen atom to which theyare bound, to form a substituted or unsubstituted heterocyclyl group. Insome such embodiments, R^(3′) is a substituted cycloalkyl group or asubstituted polycyclic cycloalkyl group. In other such embodiments,R^(1′) and R^(2′), together with the nitrogen atom to which they arebound, form a substituted or unsubstituted heterocyclyl group thatadditionally includes an O, S, or an additional N atom. In some suchembodiments R^(1′) and R^(2′), together with the nitrogen atom to whichthey are bound, form a substituted or unsubstituted piperazino,morpholino, pyrrolidino, piperidino, homopiperazino, or azepino group.

There has also been provided, in accordance with another aspect of theinvention, a composition comprising a compound according to the instantinvention and a pharmaceutically acceptable carrier.

There has also been provided, in accordance with another aspect of theinvention, a method of treating an MC4-R mediated disease, comprisingadministering to a subject in need thereof, a compound or composition ofthe instant invention.

In one embodiment, a disease to be treated by those methods of theinstant invention is obesity or type II diabetes.

Other objects, features and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The instant invention relates to novel classes of small moleculemelanocortin-4 receptor (MC4-R) agonists. These compounds can beformulated into compositions and are useful in activating MC4-R, or inthe treatment of MC4-R-mediated diseases, such as obesity, type IIdiabetes, erectile dysfunction, polycystic ovary disease, complicationsresulting from or associated with obesity and diabetes, and Syndrome X.

The following definitions are used throughout this specification.

Alkyl groups include straight chain and branched alkyl groups having 1to about 8 carbon atoms. Examples of straight chain alkyl groups includemethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl groups.Examples of branched alkyl groups, include, but not limited to,isopropyl, sec-butyl, t-butyl, and isopentyl groups. Representativesubstituted alkyl groups may be substituted one or more times with, forexample, amino, thio, alkoxy, or halo groups such as F, Cl, Br, and Igroups.

Cycloalkyl groups are cyclic alkyl groups such as, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl groups. Cycloalkyl groups also includes rings that aresubstituted with straight or branched chain alkyl groups as definedabove, and further include cycloalkyl groups that are substituted withother rings including fused rings such as, but not limited to,decalinyl, tetrahydronaphthyl, and indanyl. Cycloalkyl groups alsoinclude polycyclic cycloalkyl groups such as, but not limited to,norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenylgroups. Representative substituted cycloalkyl groups may bemono-substituted or substituted more than once, such as, but not limitedto, 2,2-, 2,3-, 2,4-2,5- or 2,6-disubstituted cyclohexyl groups ormono-, di- or tri-substituted norbornyl or cycloheptyl groups, which maybe substituted with, for example, alkyl, alkoxy, amino, thio, or halogroups.

Alkenyl groups are straight chain, branched or cyclic lower alkyl groupshaving 2 to about 8 carbon atoms, and further including at least onedouble bond, as exemplified, for instance, by vinyl, propenyl,2-butenyl, 3-butenyl, isobutenyl, cyclohexenyl, cyclopentenyl,cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl groups amongothers.

Alkynyl groups are straight chain or branched lower alkyl groups having2 to about 8 carbon atoms, and further including at least one triplebond, as exemplified by groups, including, but not limited to, ethynyl,propynyl, and butynyl groups.

Aryl groups are cyclic aromatic hydrocarbons that do not containheteroatoms. Thus aryl groups include, but are not limited to, phenyl,azulene, heptalene, biphenylene, indacene, fluorene, phenanthrene,triphenylene, pyrene, naphthacene, chrysene, biphenyl, anthracenyl, andnaphthenyl groups. Although the phrase “aryl groups” includes groupscontaining fused rings, such as fused aromatic-aliphatic ring systems,it does not include aryl groups that have other groups, such as alkyl orhalo groups, bonded to one of the ring members. Rather, groups such astolyl are referred to as substituted aryl groups. The phrase “arylgroups” includes groups bonded to one or more carbon atom(s), and/ornitrogen atom(s), in the compounds of formulas I and II. Representativesubstituted aryl groups may be mono-substituted or substituted more thanonce, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substitutedphenyl or benzyl groups, which may be substituted with groups including,but not limited to, amino, alkoxy, alkyl, or halo.

Cycloalkylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to acycloalkyl group as defined above.

Arylalkyl groups are alkyl groups as defined above in which a hydrogenor carbon bond of an alkyl group is replaced with a bond to an arylgroup as defined above.

Heterocyclyl groups are nonaromatic ring compounds containing 3 or morering members, of which, one or more is a heteroatom such as, but notlimited to, N, O, and S. The phrase “heterocyclyl group” includes fusedring species including those comprising fused aromatic and nonaromaticgroups. The phrase also includes polycyclic ring systems containing aheteroatom such as, but not limited to quinuclidyl. However, the phrasedoes not include heterocyclyl groups that have other groups, such asalkyl or halo groups, bonded to one of the ring members. Rather, theseare referred to as “substituted heterocyclyl groups”. Heterocyclylgroups include, but are not limited to, piperazino, morpholino,thiomorpholino, pyrrolidino, piperidino and homopiperazino groups.Representative substituted hetetocyclyl groups may be mono-substitutedor substituted more than once, such as, but not limited to morpholino orpiperazino groups, which are 2-, 3-, 4-, 5-, or 6-substituted, ordisubstituted with groups including, but not limited to, amino, alkoxy,alkyl, or halo.

Heteroaryl groups are aromatic ring compounds containing 3 or more ringmembers, of which, one or more is a heteroatom such as, but not limitedto, N, O, and S. Heteroaryl groups include, but are not limited to,groups such as furan, thiophene, pyrrole, isopyrrole, diazole,imidazole, isoimidazole, triazole, dithiole, oxathiole, isoxazole,oxazole, thiazole, isothiazole, oxadiazole, oxatriazole, dioxazole,oxathiazole, pyran, dioxin, pyridine, pyrimidine, pyridazine, pyrazine,triazine, oxazine, isoxazine, oxathiazine, azepin, oxepin, thiepin,diazepine, benzofuran, and isobenzofuran. Although the phrase“heteroaryl groups” includes fused ring compounds, the phrase does notinclude heteroaryl groups that have other groups bonded to one of thering members, such as alkyl groups. Rather, heteroaryl groups with suchsubstitution are referred to as “substituted heteroaryl groups”.Representative substituted heteroaryl groups may be substituted one ormore times with groups including, but not limited to, amino, alkoxy,alkyl, or halo.

Heterocyclylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheterocyclyl group as defined above.

Heteroarylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheteroaryl group as defined above.

Aminocarbonyl groups are groups of the formula RR′NC(O)—, wherein R orR′ may be the same or different, and each is independently selected fromH, or substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclylor heteroaryl groups, as defined above.

In general, “substituted” refers to a group as defined above in whichone or more bonds to a hydrogen atom contained therein are replaced by abond to non-hydrogen or non-carbon atoms such as, but not limited to, ahalogen atom such as F, Cl, Br, and I; an oxygen atom in groups such ashydroxyl groups, alkoxy groups, aryloxy groups, and ester groups; asulfur atom in groups such as thiol groups, alkyl and aryl sulfidegroups, sulfone groups, sulfonyl groups, and sulfoxide groups; anitrogen atom in groups such as amines, amides, alkylamines,dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides,imides, and enamines; a silicon atom in groups such as in trialkylsilylgroups, dialkylarylsilyl groups, alkyldiarylsilyl groups, andtriarylsilyl groups; and other heteroatoms in various other groups.Substituted alkyl groups and also substituted cycloalkyl groups alsoinclude groups in which one or more bonds to a carbon(s) or hydrogen(s)atom is replaced by a bond to a heteroatom such as oxygen in carbonyl,carboxyl, and ester groups; nitrogen in groups such as imines, oximes,hydrazones, and nitriles.

Substituted cycloalkyl, substituted aryl, substituted heterocyclyl andsubstituted heteroaryl also include rings and fused ring systems inwhich a bond to a hydrogen atom is replaced with a bond to a carbonatom. Therefore, substituted cycloalkyl, substituted aryl, substitutedheterocyclyl and substituted heteroaryl groups may be substituted withalkyl groups as defined above.

Pharmaceutically acceptable salts include a salt with an inorganic base,organic base, inorganic acid, organic acid, or basic or acidic aminoacid. As salts of inorganic bases, the invention includes, for example,alkali metals such as sodium or potassium, alkali earth metals such ascalcium and magnesium or aluminum, and ammonia. As salts of organicbases, the invention includes, for example, trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine. As salts of inorganic acids, the instant inventionincludes, for example, hydrochloric acid, hydroboric acid, nitric acid,sulfuric acid, and phosphoric acid. As salts of organic acids, theinstant invention includes, for example, formic acid, acetic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, malic acid, methanesulfonic acid,benzenesulfonic acid, and p-toluenesulfonic acid. As salts of basicamino acids, the instant invention includes, for example, arginine,lysine and ornithine. Acidic amino acids include, for example, asparticacid and glutamic acid.

Prodrugs, as used in the context of the instant invention, includesthose derivatives of the instant compounds which undergo in vivometabolic biotransformation, by enzymatic or nonenzymatic processes,such as hydrolysis, to form a compound of the invention. Prodrugs can beemployed to improve pharmaceutical or biological properties, as forexample solubility, melting point, stability and related physicochemicalproperties, absorption, pharmacodynamics and other delivery-relatedproperties.

The instant invention provides potent and specific agonists of MC4-Rthat are low molecular weight small molecules. In accordance with oneaspect of the invention, the invention provides compounds ofA¹-A²-A³-A⁴. Compounds of the invention further include prodrugs ofcompounds of formula A¹-A²-A³-A⁴, pharmaceutically acceptable saltsthereof, stereoisomers thereof, tautomers thereof, hydrates thereof,hydrides thereof, or solvates thereof.

In compounds of formula A¹-A²-A³-A⁴, A¹ is a group of formula IIA orIIB.

In compounds of formula A¹-A²-A³-A⁴, R^(1′) is selected from the groupconsisting of H, and substituted and unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl,heteroarylalkyl, and cycloalkylalkyl groups, and R^(2′) is selected fromthe group consisting of substituted and unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl,heteroarylalkyl, and cycloalkylalkyl groups. In compounds of formulaA¹-A²-A³-A⁴, R^(1′) and R^(2′), together with the nitrogen atom to whichthey are both bound, may alternatively form a substituted orunsubstituted heterocyclyl or heteroaryl group. In one embodiment ofcompounds of formula A¹-A²-A³-A⁴, R^(1′) is H and R^(2′) is selectedfrom the group consisting of substituted and unsubstituted alkyl,arylalkyl, and heteroarylalkyl groups. In still other embodiments ofcompounds of formula A¹-A²-A³-A⁴, R^(1′) is H and R^(2′) is selectedfrom the group consisting of substituted and unsubstituteddialkylaminoethyl, 4-ethylbenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl,3-methylbenzyl, benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl,and thiophene groups. In still further embodiments of compounds offormula A¹-A²-A³-A⁴, R^(1′) and R^(2′) may be the same or different andare each independently selected from the group consisting of substitutedand unsubstituted alkyl, arylalkyl, and heteroarylalkyl groups. In yetother embodiments of compounds of formula A¹-A²-A³-A⁴, R^(1′) and R^(2′)may be the same or different and are each independently selected fromthe group consisting of substituted and unsubstituted dialkylaminoethyl,4-ethylbenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl, 3-methylbenzyl,benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl, and thiophenegroups. In still other embodiments of compounds of formula A¹-A²-A³-A⁴,R^(1′) and R^(2′), together with the nitrogen to which they are bound,form a substituted or unsubstituted heterocyclyl group. In otherembodiments of compounds of formula A¹-A²-A³-A⁴, R^(1′) and R^(2′),together with the nitrogen to which they are bound, form a substitutedor unsubstituted saturated heterocyclyl group comprising at least oneheteroatom selected from the group consisting of O, S, and N, inaddition to the nitrogen atom to which R^(1′) and R^(2′) are bound. Inanother embodiment of compounds of formula A¹-A²-A³-A⁴, R^(1′) andR^(2′), together with the nitrogen atom to which they are bound, form asubstituted or unsubstituted heterocyclyl ring containing at least twonitrogen atoms. In still another embodiment of compounds of formulaA¹-A²-A³-A⁴, R^(1′) and R^(2′), together with the nitrogen atom to whichthey are bound, form a substituted or unsubstituted heterocyclyl ringcontaining at least one oxygen atom and one nitrogen atom. In yet otherembodiments of compounds of formula A¹-A²-A³-A⁴, R^(1′) and R^(2′),together with the nitrogen to which they are bound, form a substitutedor unsubstituted piperazino, morpholino, pyrrolidino, piperidino,homopiperazino, or azepino group. In still further embodiments ofcompounds of formula A¹-A²-A³-A⁴, R^(1′) and R^(2′), together with thenitrogen to which they are bound, form a piperazino group optionallysubstituted by one or two alkyl groups or in one embodiment by one ortwo methyl groups.

In compounds of formula A¹-A²-A³-A⁴, R³ is selected from the groupconsisting of substituted and unsubstituted aryl, alkyl, alkenyl,alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl,arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups. In oneembodiment of compounds of formula A¹-A²-A³-A⁴, R^(3′) is selected fromthe group consisting of substituted and unsubstituted cycloalkyl,polycyclic cycloalkyl, alkenyl, alkyl, and aryl groups. In still otherembodiments of compounds of formula A¹-A²-A³-A⁴, R^(3′) is selected fromthe group consisting of substituted and unsubstituted cyclohexyl,2-alkylcyclohexyl, 2,2-dialkylcyclohexyl, 2,3-dialkylcyclohexyl,2,4-dialkylcyclohexyl, 2,5-dialkylcyclohexyl, 2,6-dialkylcyclohexyl,3,4-dialkylcyclohexyl, 3-alkylcyclohexyl, 4-alkylcyclohexyl,3,3,5-trialkylcyclohexyl, cyclohexylmethyl, 2-aminocyclohexyl,3-aminocyclohexyl, 4-aminocyclohexyl, 2,3-diaminocyclohexyl,2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl, 2,5-diaminocyclohexyl,2,6-diaminocyclohexyl, 2,2-diaminocyclohexyl, 2-alkoxycyclohexyl,3-alkoxycyclohexyl, 4-alkoxycyclohexyl, 2,3-dialkoxycyclohexyl,2,4-dialkoxycyclohexyl, 3,4-dialkoxycyclohexyl, 2,5-dialkoxycyclohexyl,2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl, 2-alkylthiocyclohexyl,3-alkylthiocyclohexyl, 4-alkylthiocyclohexyl, 2,3-dialkylthiocyclohexyl,2,4-dialkylthiocyclohexyl, 3,4-dialkylthiocyclohexyl,2,5-dialkylthiocyclohexyl, 2,6-dialkylthiocyclohexyl,2,2-dialkylthiocyclohexyl, cyclopentyl, cycloheptyl, cyclohexenyl,isopropyl, n-butyl, cyclooctyl, 2-arylcyclohexyl, 2-phenylcyclohexyl,2-arylalkylcyclohexyl, 2-benzylcyclohexyl, 4-phenylcyclohexyl,adamantyl, isocamphenyl, carenyl, 7,7-dialkylnorbornyl, bornyl,norbornyl, and decalinyl groups. In still other embodiments of compoundsof formula A¹-A²-A³-A⁴, R^(3′) is selected from the group consisting ofsubstituted and unsubstituted cyclohexyl, 2-methylcyclohexyl,2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl,2,5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl, 3,4-dimethylcyclohexyl,3-methylcyclohexyl, 4-methylcyclohexyl, cyclohexenyl,3,3,5-trimethylcyclohexyl, 4-t-butylcyclohexyl, cyclohexylmethyl,isopinocampheyl, 7,7-dimethylnorbornyl, 4-isopropylcyclohexyl, and3-methylcycloheptyl groups.

In compounds of formula A¹-A²-A³-A⁴, R⁴ is selected from the groupconsisting of H, and substituted and unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl,heteroaryl, heterocyclyl, arylalkyl, and heteroarylalkyl groups. In oneembodiment of compounds of formula A¹-A²-A³-A⁴, R^(4′) is H.

In compounds of formula A¹-A²-A³-A⁴, A² is selected from the groupconsisting of substituted and unsubstituted aryl groups and substitutedand unsubstituted heteroaryl groups. In one embodiment of compounds offormula A¹-A²-A³-A⁴, A² is selected from the group consisting ofsubstituted and unsubstituted phenyl groups and substituted andunsubstituted pyridyl groups. In another embodiment, A² is a substitutedor unsubstituted phenyl group and A¹ and A³ are ortho to one another onthe A² phenyl group. In another embodiment, A² is a substituted orunsubstituted phenyl group and A¹ and A³ are para to one another on theA² phenyl group. In another embodiment, A² is a substituted orunsubstituted phenyl group and A¹ and A³ are meta to one another on theA² phenyl group. In another embodiment, A² is a substituted orunsubstituted phenyl group, A³ is a covalent bond, and A¹ and A⁴ areortho to one another on the A² phenyl group. In another embodiment, A²is a substituted or unsubstituted phenyl group, A³ is a covalent bond,and A¹ and A⁴ are para to one another on the A² phenyl group. In yetanother embodiment, A² is a substituted or unsubstituted phenyl group,A³ is a covalent bond, and A¹ and A⁴ are meta to one another on the A²phenyl group.

In compounds of formula A¹-A²-A³-A⁴, A³ is a covalent bond such that A²is directly bonded to A⁴. Alternatively, in compounds of formulaA¹-A²-A³-A⁴, A³ is a linking group selected from the group consisting ofO, S, —NR^(a)—, —C(═O)—, —C(═O)O—, —NR^(a)C(═O)—, —SO₂NR^(a)—, —C(═S)—,—C(═O)S—, P(═O)R^(b)—, —SO₂—, and —S(═O)—. If A³ is a linking group,then it is bonded to A² and A⁴ in a configuration selected from thegroup consisting of A²-O-A⁴, A²-S-A⁴, A²-NR^(a)-A⁴, A²C(═O)-A⁴,A²-C(═O)O-A⁴, A⁴-C(═O)O-A², A²-NR^(a)C(═O)-A⁴, A⁴-NR^(a)C(═O)-A²,A²-SO₂NR^(a)-A⁴, A⁴-SO₂NR^(a)-A², A²-C(═S)-A⁴, A²-(C═O)S-A⁴,A⁴-(C═O)S-A², A²-(P═O)R^(b)-A⁴, A²-SO₂-A⁴, and A²-S(═O)-A⁴. In compoundsof formula A¹-A²-A³-A⁴, if A³ is a linking group with the configurationA⁴-NR^(a)C(═O)-A², then A² is not a substituted or unsubstituted phenylgroup and is not a substituted or unsubstituted 6-membered N-containingheteroaryl group. In one embodiment of compounds of formula A¹-A²-A³-A⁴,A³ is a linking group such that A² is directly bonded to A⁴. In someembodiments, A³ is a linking group bonded to A² and A⁴ in aconfiguration selected from the group consisting of A²-NR^(a)-A⁴,A²-C(═O)-A⁴, A²-C(═O)O-A⁴, A⁴-C(═O)O-A², A²-NHC(═O)-A⁴, A²-SO₂NH-A⁴, andA²-SO₂-A⁴.

In compounds of formula A¹-A²-A³-A⁴, A⁴ is selected from the groupconsisting of substituted and unsubstituted arylalkyl, heteroarylalkyl,aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl,cycloalkylalkyl, alkenyl, alkynyl, and alkyl groups. In one embodimentof compounds of formula A¹-A²-A³-A⁴, A⁴ is a 2,4-disubstitutedphenylethyl group or an indolylethyl group. In still other embodimentsof compounds of formula A¹-A²-A³-A⁴, A⁴ is selected from the groupconsisting of 2,4-dihalophenylethyl, and 2,4-dialkylphenylethyl groups.In still other embodiments of compounds of formula A¹-A²-A³-A⁴, A⁴ isselected from the group consisting of phenylethyl,2,4-dichlorophenylethyl, 4-methoxyphenylethyl, 4-bromophenylethyl,4-methylphenylethyl, 4-chlorophenylethyl, 4-ethylphenylethyl,cyclohexenylethyl, 2-methoxyphenylethyl, 2-chlorophenylethyl,2-fluorophenylethyl, 3-methoxyphenyl-ethyl, 3-fluorophenylethyl,thienylethyl, indolylethyl, 4-hydroxyphenylethyl,3,4-dimethoxyphenylethyl, 2-chloro-4-iodophenylethyl,2-fluoro-4-methylphenylethyl, 2-fluoro-4-bromophenylethyl,2-fluoro-4-methoxyphenylethyl, 2-trifluoromethyl-4-fluorophenylethyl,2,4-difluorophenylethyl, 2,4-dimethylphenylethyl, or2,4-dimethoxyphenylethyl groups.

In some embodiments of compounds of formula A¹-A²-A³-A⁴, A⁴ is asubstituted or unsubstituted arylalkyl or heteroarylalkyl group such asa substituted arylethyl, arylmethyl, heteroarylethyl, orheteroarylmethyl group, where the aryl or heteroaryl group is a groupsuch as one of those included in Table I. In Table 1, Bn is benzyl, Cpis cyclopentyl, Pr is propyl, iPr is isopropyl, Et is ethyl, Me ismethyl, Ph is phenyl, and t-Bu is t-butyl. TABLE 1 Aryl/Heteroaryl GroupR^(a′), R^(b′)

R^(a′) = —H, —Cl, —F, —Br, —I, —CN, —Me, —Ph, —NHMe, —SH, —SMe, —OMe,—CH₂SO₂Ph, or —OCp

R^(a′) = —F, —Cl, —Br, —I, —CN, —NO₂, —ON, —OMe, —Me, or —Ph

R^(a′) = —F, —Cl, —Br, —I, —OMe, —OBn, —CF₃, —CN, —NO₂, —Me, —Ph, or—tBu

R^(a′) = —OMe; and R^(b′) = —OMe

R^(a′) = —OMe, —OEt, —OPr, —OiPr, —OCp, —CF₃, —Me, —Br, or —Cl; andR^(b′) = —OMe, —Me, —Ph, —tBu, —F, —Cl, —Br, —I, —NO₂, —CN, —CF₃, or—C(═O)CH₃

R^(a′) = —Me or —Cl; and R^(b′) = —Me or —Cl

R^(a′) = —CF₃ or —OMe; and R^(b′) = —CF₃ or —OMe

R^(a′) = —F, —Cl, or —OMe; and R^(b′) = —F, —Cl, OMe, or —Br

Not Applicable

Not Applicable

R^(a′) = —H or —Cl; and R^(b′) = —OMe or —F

Not Applicable

R^(a′) = H or CF₃

R^(a′) = H or CF₃

Not Applicable

R^(a′) = —H, —F, or —Br; R^(b′) = —H, —OMe, —OEt, —OPr, —OiPr, or —OCp;and R^(c′) = —H, —F, or —Me

Not Applicable

R^(a′) = —H or —OMe

R^(a′) = —H, —Cl, or —CF₃; and R^(b′) = —H or —Br

R^(a) = —H or —Me; R^(b′) = —H or —Me; and R^(c′) = —H or —Cl

Not applicable

Not applicable

R^(a′) = —H or —Cl; and R^(b′) = —H or —Cl

R^(a′) = —H or —OBn

R^(a′) —H or —SMe

Not applicable

In compounds of formula A¹-A²-A³-A⁴, R^(a) is selected from the groupconsisting of H, and substituted and unsubstituted arylalkyl,heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, and alkyl groups.In one embodiment of compounds of formula A¹-A²-A³-A⁴, R^(a) is H.

In compounds of formula A¹-A²-A³-A⁴, R^(b) is selected from the groupconsisting of substituted and unsubstituted arylalkyl, heteroarylalkyl,aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl,cycloalkylalkyl, alkenyl, alkynyl, and alkyl groups.

In accordance with one aspect of the invention, the invention provides afirst group of compounds of formula I such as shown below.

Compounds of the invention further include prodrugs of the first groupof compounds of formula I, pharmaceutically acceptable salts thereof,stereoisomers thereof, tautomers thereof, hydrates thereof, hydridesthereof, or solvates thereof.

In the first group of compounds of formula I, Q, W, X, Y, and Z areindependently selected from the group consisting of carbon atoms andnitrogen atoms. In some embodiments of the compounds of formula I, atleast one of Q, W, X, Y, and Z is a nitrogen atom. In other embodimentsof the compounds of formula I, Q, W, X, Y, and Z are all carbon atoms.In other embodiments of the compounds of formula I, Q is a nitrogen atomand W, X, Y, and Z are all carbon atoms. In other embodiments of thecompounds of formula I, W is a nitrogen atom and Q, X, Y, and Z are allcarbon atoms. In other embodiments of the compounds of formula I, X is anitrogen atom and Q, W, Y, and Z are all carbon atoms. In still otherembodiments of the compounds of formula I, Y is a nitrogen atom and Q,W, X, and Z are all carbon atoms. In still other embodiments of thecompounds of formula I, Z is a nitrogen atom and Q, W, X, and Y are allcarbon atoms.

In the first group of compounds of formula I, R¹, R², R³, R⁴, and R⁵ maybe the same or different, and are each independently selected from thegroup consisting of H, Cl, I, F, Br, OH, NH₂, CN, NO₂, and substitutedand unsubstituted aryl, alkoxy, amino, alkyl, alkenyl, alkynyl,alkylamino, dialkylamino, cycloalkyl, heterocyclylamino,heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, heteroarylaminocarbonyl groups, and groups offormula IIA or IIB.

In the first group of compounds of formula I, R¹ may be absent if W is anitrogen atom; R² may be absent if X is a nitrogen atom; R³ may beabsent if Z is a nitrogen atom; R⁴ may be absent if Y is a nitrogenatom; and R⁵ may be absent if Q is a nitrogen atom. In the first groupof compounds of formula I, at least one of R¹, R², R³, R⁴, or R⁵ is agroup having the formula IIA or IIB. In some embodiments of the firstgroup of compounds of formula I, Q is a carbon atom and R⁵ is a grouphaving the formula IIA or IIB. In one embodiment, four of R¹ through R⁵are H, and one of R¹ through R⁵ is a group of formula IIA or IIB. Inother embodiments, three of R¹ through R⁵ are H, one of R¹ through R⁵ isabsent, one of R¹ through R⁵ is a group of formula IIA or IIB, one of W,Q, X, Y, and Z is a nitrogen atom, and four of W, Q, X, Y, and Z arecarbon atoms.

In the first group of compounds of formula I, R^(1′) is selected fromthe group consisting of H, and substituted and unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl,heteroarylalkyl, and cycloalkylalkyl groups, and R^(2′) is selected fromthe group consisting of substituted and unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl,heteroarylalkyl, and cycloalkylalkyl groups. In the first group ofcompounds of formula I, R^(1′) and R^(2′), together with the nitrogenatom to which they are both bound, may alternatively form a substitutedor unsubstituted heterocyclyl or heteroaryl group. In one embodimentR^(1′) is H and R^(2′) is selected from the group consisting ofsubstituted and unsubstituted alkyl, arylalkyl, and heteroarylalkylgroups. In still other embodiments, R^(1′) is H and R^(2′) is selectedfrom the group consisting of substituted and unsubstituteddialkylaminoethyl, 4-ethylbenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl,3-methylbenzyl, benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl,and thiophene groups. In still further embodiments, R^(1′)and R^(2′) maybe the same or different and are each independently selected from thegroup consisting of substituted and unsubstituted alkyl, arylalkyl, andheteroarylalkyl groups. In yet other embodiments, R^(1′) and R^(2′) maybe the same or different and are each independently selected from thegroup consisting of substituted and unsubstituted dialkylaminoethyl,4-ethylbenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl, 3-methylbenzyl,benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl, and thiophenegroups. In still other embodiments, R^(1′) and R^(2′), together with thenitrogen to which they are bound, form a substituted or unsubstitutedheterocyclyl group. In other embodiments, R^(1′) and R^(2′), togetherwith the nitrogen to which they are bound, form a substituted orunsubstituted saturated heterocyclyl group comprising at least oneheteroatom selected from the group consisting of O, S, and N, inaddition to the nitrogen atom to which R^(1′) and R^(2′) are bound. Inanother embodiment, R^(1′) and R^(2′), together with the nitrogen atomto which they are bound, form a substituted or unsubstitutedheterocyclyl ring containing at least two nitrogen atoms. In stillanother embodiment, R^(1′) and R^(2′), together with the nitrogen atomto which they are bound, form a substituted or unsubstitutedheterocyclyl ring containing at least one oxygen atom and one nitrogenatom. In yet other embodiments, R^(1′) and R^(2′), together with thenitrogen to which they are bound, form a substituted or unsubstitutedpiperazino, morpholino, pyrrolidino, piperidino, homopiperazino, orazepino group. In still further embodiments, R^(1′) and R^(2′), togetherwith the nitrogen to which they are bound, form a piperazino groupoptionally substituted by one or two alkyl groups or in one embodimentby one or two methyl groups.

In the first group of compounds of formula I, R^(3′) is selected fromthe group consisting of substituted and unsubstituted aryl, alkyl,alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl,heterocyclylalkyl, arylalkyl, heteroarylalkyl, and cycloalkylalkylgroups. In one embodiment of the first group of compounds of formula I,R^(3′) is selected from the group consisting of substituted andunsubstituted cycloalkyl, polycyclic cycloalkyl, alkenyl, alkyl, andaryl groups. In still other embodiments, R^(3′) is selected from thegroup consisting of substituted and unsubstituted cyclohexyl,2-alkylcyclohexyl, 2,2-dialkylcyclohexyl, 2,3-dialkylcyclohexyl,2,4-dialkylcyclohexyl, 2,5-dialkylcyclohexyl, 2,6-dialkylcyclohexyl,3,4-dialkylcyclohexyl, 3-alkylcyclohexyl, 4-alkylcyclohexyl,3,3,5-trialkylcyclohexyl, cyclohexylmethyl, 2-aminocyclohexyl,3-aminocyclohexyl, 4-aminocyclohexyl, 2,3-diaminocyclohexyl,2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl, 2,5-diaminocyclohexyl,2,6-diaminocyclohexyl, 2,2-diaminocyclohexyl, 2-alkoxycyclohexyl,3-alkoxycyclohexyl, 4-alkoxycyclohexyl, 2,3-dialkoxycyclohexyl,2,4-dialkoxycyclohexyl, 3,4-dialkoxycyclohexyl, 2,5-dialkoxycyclohexyl,2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl, 2-alkylthiocyclohexyl,3-alkylthiocyclohexyl, 4-alkylthiocyclohexyl, 2,3-dialkylthiocyclohexyl,2,4-dialkylthiocyclohexyl, 3,4-dialkylthiocyclohexyl,2,5-dialkylthiocyclohexyl, 2,6-dialkylthiocyclohexyl,2,2-dialkylthiocyclohexyl, cyclopentyl, cycloheptyl, cyclohexenyl,isopropyl, n-butyl, cyclooctyl, 2-arylcyclohexyl, 2-phenylcyclohexyl,2-arylalkylcyclohexyl, 2-benzylcyclohexyl, 4-phenylcyclohexyl,adamantyl, isocamphenyl, carenyl, 7,7-dialkylnorbornyl, bornyl,norbornyl, and decalinyl groups. In still other embodiments, R^(3′) isselected from the group consisting of substituted and unsubstitutedcyclohexyl, 2-methylcyclohexyl, 2,2-dimethylcyclohexyl,2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl,2,6-dimethylcyclohexyl, 3,4-dimethylcyclohexyl, 3-methylcyclohexyl,4-methylcyclohexyl, cyclohexenyl, 3,3,5-trimethylcyclohexyl,4-t-butylcyclohexyl, cyclohexylmethyl, isopinocampheyl,7,7-dimethylnorbornyl, 4-isopropylcyclohexyl, and 3-methylcycloheptylgroups. In some embodiments, R^(3′) is a substituted cyclohexyl groupsuch as a trifluoromethyl substituted cyclohexyl group such as a4-trifluoromethylcyclohexyl group.

In the first group of compounds of formula I, R^(4′) is selected fromthe group consisting of H, and substituted and unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl,heteroaryl, heterocyclyl, arylalkyl, and heteroarylalkyl groups. In oneembodiment, R⁴ is H.

In the first group of compounds of formula I, R⁶ is a group of formulaIIIA, IIIB, IIIC, IIID, or IIIE.

In some embodiments, R⁶ has the formula IIIA. In other embodiments, R⁶has the formula IIIB. In still other embodiments, R⁶ has the formulaIIIC. In other embodiments, R⁶ has the formula IIID. In still otherembodiments, R⁶ has the formula IIIE.

In the first group of compounds of formula I in which R⁶ is a group offormula IIIA, m is an integer selected from 0, 1, or 2, and n is aninteger selected from 0, 1, or 2. In some embodiments where R⁶ has theformula IIIA, m is 0 and n is 2. In other embodiments where R⁶ has theformula IIIA, m is 1 and n is 1. In still other embodiments where R⁶ hasthe formula IIIA, m is 0 and n is 1. In yet other embodiments where R⁶has the formula IIIA, m is 2 and n is 1. Examples of compounds in whichm is 0 and n is 2, in which m is 1 and n is 1, in which m is 0 and n is1, and in which m is 2 and n is 1 are respectively shown below ascompounds of formula IVA, IVB, IVC, and IVD. In compounds of formula IVAthrough IVD, R¹ through R⁵, R⁷ through R⁹, Q, W, X, Y, Z, and R^(1′)through R^(4′) have the same definitions set forth elsewhere in thisdocument.

In the first group of compounds of formula I in which R⁶ is a group offormula IIIA or IIIB, R⁷, R⁸, R⁹, and R¹⁰ may be the same or differentand are independently selected from the group consisting of H, Cl, I, F,Br, OH, NH₂, CN, NO₂, and substituted and unsubstituted alkoxy, amino,alkyl, aryl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups. In thefirst group of compounds of formula I in which R⁶ is a group of formulaIIIA or IIIB, R⁷ and R⁸ may alternatively join together with the carbonatoms to which they are attached to form a substituted or unsubstituted5 or 6 membered ring. In some embodiments in which R⁶ is a group offormula IIIA or IIIB, at least one of R⁸ or R⁹ is selected form thegroup consisting of Br, Cl, F, I, and substituted and unsubstitutedalkyl groups, and alkoxy groups.

In the first group of compounds of formula I in which R⁶ is a group offormula IIIB, R¹¹ is selected from the group consisting of H, andsubstituted and unsubstituted alkyl groups.

In the first group of compounds of formula I in which R⁶ is a group offormula IIIB, R¹², R¹³, R¹⁴, and R¹⁵ may be the same or different andare independently selected from the group consisting of H, Cl, I, F, Br,OH, NH₂, CN, NO₂, and substituted and unsubstituted alkoxy, amino,alkyl, aryl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups. In thefirst group of compounds of formula I in which R⁶ is a group of formulaIIIB, R¹⁶ is selected from the group consisting of H, and substitutedand unsubstituted alkyl groups. In the first group of compounds offormula I in which R⁶ is a group of formula IIIB, R¹² and R¹⁴ mayalternatively represent a second bond between the carbon bonded to R¹²and the carbon bonded to R¹⁴ such that the bond between the carbonbonded to R¹² and the carbon bonded to R¹⁴ is a double bond or is a bondof an aromatic ring. Such compounds have the formula VA. Furthermore, inthe first group of compounds of formula I in which R⁶ is a group offormula IIIB, R¹¹ and R¹⁶ may represent a second bond between the carbonbonded to R¹⁶ and the nitrogen bonded to R¹¹ such that the bond betweenthe carbon bonded to R¹⁶ and the nitrogen bonded to R¹¹ is a double bondor is a bond of an aromatic ring. Such compounds have the formula VB. Instill other compounds of formula I, R¹² and R¹⁴ represent a second bondbetween the carbon bonded to R¹² and the carbon bonded to R¹⁴ such thatthe bond between the carbon bonded to R¹² and the carbon bonded to R¹⁴is a double bond or is a bond of an aromatic ring, and R¹¹ and R¹⁶represent a second bond between the carbon bonded to R¹⁶ and thenitrogen bonded to R¹¹ such that the bond between the carbon bonded toR¹⁶ and the nitrogen bonded to R¹¹ is a double bond or is a bond of anaromatic ring. Such compounds have the formula VC. In some embodimentsin which R⁶ is a group of formula IIIB, R¹¹ is H or a substituted orunsubstituted alkyl group, and R¹⁶ is H. The variables in the compoundsof formula VA, VB, and VC have the same definitions as describedelsewhere in this document.

In the first group of compounds of formula I in which R⁶ is a group offormula IIIC, R¹⁷ is selected from the group consisting of H, andsubstituted and unsubstituted arylalkyl, heteroarylalkyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl,cycloalkylalkyl, alkenyl, alkynyl, and alkyl groups. In someembodiments, if R¹⁷ is H or an unsubstituted alkyl group, then R^(1′)and R^(2′) join together, with the nitrogen atom to which they arebound, to form a substituted or unsubstituted heterocyclyl group. Insome such embodiments, R^(3′) is a substituted cycloalkyl group or asubstituted polycyclic cycloalkyl group. In other such embodiments,R^(1′) and R^(2′), together with the nitrogen atom to which they arebound, form a substituted or unsubstituted heterocyclyl group thatadditionally includes an O, S, or an additional N atom. In some suchembodiments R^(1′) and R^(2′), together with the nitrogen atom to whichthey are bound, form a substituted or unsubstituted piperazino,morpholino, pyrrolidino, piperidino, homopiperazino, or azepino group.

In the first group of compounds of formula I in which R⁶ is a group offormula IIID or IIIE, R¹⁸ is selected from the group consisting of H,and substituted and unsubstituted arylalkyl, heteroarylalkyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl,cycloalkylalkyl, alkenyl, alkynyl, and alkyl groups. In some embodimentsin which R⁶ is a group of formula IIID, R¹⁸ is H. In some embodiments inwhich R⁶ is a group of formula IIIE, R¹⁸ is H.

In the first group of compounds of formula I in which R⁶ is a group offormula IIID or IIIE, R¹⁹ is selected from the group consisting ofsubstituted and unsubstituted arylalkyl, heteroarylalkyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl,cycloalkylalkyl, alkenyl, alkynyl, and alkyl groups. In some embodimentsin which R⁶ is a group of formula IIID, R¹⁹ is a substituted arylalkylgroup, and the alkyl group of the R¹⁹ arylalkyl group is substitutedwith an amino or acetamido group.

In some embodiments in which R⁶ is a group of formula IIIC, IIID, orIIIE, R¹⁷ or R¹⁹ is selected from the group consisting of substitutedand unsubstituted arylalkyl, alkenyl, heteroarylalkyl, andheterocyclylalkyl groups. In other embodiments in which R⁶ is a group offormula IIIC, IIID, or IIIE, R¹⁷ or R¹⁹ is selected from the groupconsisting of substituted and unsubstituted arylalkyl groups, andsubstituted and unsubstituted heteroarylalkyl groups. In otherembodiments in which R⁶ is a group of formula IIIC, IIID, or IIIE, R¹⁷or R¹⁹ is a substituted or unsubstituted phenylalkyl group or asubstituted or unsubstituted indolylalkyl group. In still otherembodiments in which R⁶ is a group of formula IIIC, IIID, or IIIE, R¹⁷or R¹⁹ is a 2,4-disubstituted phenylethyl group or an indolylethylgroup. In still other embodiments in which R⁶ is a group of formulaIIIC, IIID, or IIIE, R¹⁷ or R¹⁹ is selected from the group consisting of2,4-dihalophenylethyl, and 2,4-dialkylphenylethyl groups. In still otherembodiments in which R⁶ is a group of formula IIIC, IIID, or IIIE, R¹⁷or R¹⁹ is selected from the group consisting of phenylethyl,2,4-dichlorophenylethyl, 4-methoxyphenylethyl, 4-bromophenylethyl,4-methylphenylethyl, 4-chlorophenylethyl, 4-ethylphenylethyl,cyclohexenylethyl, 2-methoxyphenylethyl, 2-chlorophenylethyl,2-fluorophenylethyl, 3-methoxyphenylethyl, 3-fluorophenylethyl,thienylethyl, indolylethyl, 4-hydroxyphenylethyl,3,4-dimethoxyphenylethyl, 2-chloro-4-iodophenylethyl,2-fluoro-4-methylphenylethyl, 2-fluoro-4-bromophenylethyl,2-fluoro-4-methoxyphenylethyl, 2-trifluoromethyl-4-fluorophenylethyl,2,4-difluorophenylethyl, 2,4-dimethylphenylethyl, or2,4-dimethoxyphenylethyl groups. In some embodiments such as thosedescribed above in which R¹⁷ or R¹⁹ is a substituted or unsubstitutedarylalkyl group such as a substituted or unsubstituted arylethyl groupor more specifically a substituted phenylethyl group, the alkyl or ethylgroup of the substituted or unsubstituted arylalkyl group is furthersubstituted with a group such as an amino group; an alkylamino groupsuch as a methylamino group; a hydroxyalkyl group such as ahydroxymethyl group; an —N(H)C(═O)-alkyl group such as a —N(H)C(═O)—CH₃group; an —N(H)C(═O)—O-alkyl group such as a —N(H)C(═O)—O—C(CH₃)₃ group;an —N(H)C(═O)—O-arylalkyl group such as a —N(H)C(═O)—O-benzyl group; an—N(H)C(═O)-heterocyclyl group such as a—N(H)C(═O)-(1,2,3,4-tetrahydroisoquinoline) group; or an arylalkoxyalkylgroup, such as a phenylmethoxymethyl group, a 3-bromophenylmethoxymethylgroup, a 4-methylphenylmethoxymethyl group, a4-fluorophenylmethoxymethyl group, a2-fluoro-4-chlorophenylmethoxymethyl group, and the like.

In some embodiments in which R⁶ is a group of formula IIIC, IIID, orIIIE, R¹⁷ or R¹⁹ is a substituted or unsubstituted arylalkyl orheteroarylalkyl group such as a substituted arylethyl, arylmethyl,heteroarylethyl, or heteroarylmethyl group, the aryl or heteroaryl groupis a group such as one of those included in Table I above.

There has also been provided, in accordance with another aspect of theinvention, a composition comprising a compound according to the instantinvention and a pharmaceutically acceptable carrier.

There has also been provided, in accordance with another aspect of theinvention, a method of activating MC4-R in a subject, comprisingadministering to a subject in need thereof an effective amount of acompound or composition of the instant invention.

There has also been provided, in accordance with another aspect of theinvention, a method of treating an MC4-R-mediated disease, comprisingadministering to a subject in need thereof, a compound or composition ofthe instant invention.

In one embodiment, a disease to be treated by those methods of theinstant invention is obesity, or type I or type II diabetes.

In another embodiment, a condition to be treated by those methods of theinstant invention is a condition associated with or a complicationarising from obesity or type II diabetes.

In another embodiment, a condition to be treated by those methods of theinstant invention is erectile dysfunction.

In another embodiment, a disease to be treated by those methods of theinstant invention is polycystic ovary disease.

In another embodiment, a disease to be treated by those methods of theinstant invention is Syndrome X.

The invention also includes tautomers of the instant compounds. Theinstant invention also includes prodrugs, pharmaceutically acceptablesalts, stereoisomers, hydrates, hydrides, and solvates of thesetautomers.

The instant compounds may exist as one or more stereoisomers. Thevarious stereoisomers include enantiomers, diastereomers, atropisomersand geometric isomers. In some cases, one stereoisomer may be moreactive and/or may exhibit beneficial effects in comparison to otherstereoisomer(s) or when separated from the other stereoisomer(s).However, it is well within the skill of the ordinary artisan toseparate, and/or to selectively prepare said stereoisomers. Accordingly,“stereoisomers” of the instant invention necessarily includes mixturesof stereoisomers, individual stereoisomers, or optically active forms.

The instant invention also provides for compositions which may beprepared by mixing one or more compounds of the instant invention, orpharmaceutically acceptable salts or tautomers thereof, withpharmaceutically acceptable carriers, excipients, binders, diluents orthe like, to treat or ameliorate a variety of disorders. Examples ofsuch disorders include, but are not limited to obesity, erectiledisorders, cardiovascular disorders, neuronal injuries or disorders,inflammation, fever, cognitive disorders, sexual behavior disorders. Atherapeutically effective dose further refers to that amount of one ormore compounds of the instant invention sufficient to result inamelioration of symptoms of the disorder. The pharmaceuticalcompositions of the instant invention can be manufactured by methodswell known in the art such as conventional granulating, mixing,dissolving, encapsulating, lyophilizing, emulsifying or levigatingprocesses, among others. The compositions can be in the form of, forexample, granules, powders, tablets, capsules, syrup, suppositories,injections, emulsions, elixirs, suspensions or solutions. The instantcompositions can be formulated for various routes of administration, forexample, by oral administration, by intranasal administration, bytransmucosal administration, by rectal administration, or subcutaneousadministration as well as intrathecal, intravenous, intramuscular,intraperitoneal, intranasal, intraocular or intraventricular injection.The compound or compounds of the instant invention can also beadministered in a local rather than a systemic fashion, such asinjection as a sustained release formulation. The following dosage formsare given by way of example and should not be construed as limiting theinstant invention.

For oral, buccal, and sublingual administration, powders, suspensions,granules, tablets, pills, capsules, gelcaps, and caplets are acceptableas solid dosage forms. These can be prepared, for example, by mixing oneor more compounds of the instant invention, or pharmaceuticallyacceptable salts or tautomers thereof, with at least one additive orexcipient such as a starch or other additive. Suitable additives orexcipients are sucrose, lactose, cellulose sugar, mannitol, maltitol,dextran, sorbitol, starch, agar, alginates, chitins, chitosans, pectins,tragacanth gum, gum arabic, gelatins, collagens, casein, albumin,synthetic or semi-synthetic polymers or glycerides, methyl cellulose,hydroxypropylmethyl-cellulose, and/or polyvinylpyrrolidone. Optionally,oral dosage forms can contain other ingredients to aid inadministration, such as an inactive diluent, or lubricants such asmagnesium stearate, or preservatives such as paraben or sorbic acid, oranti-oxidants such as ascorbic acid, tocopherol or cysteine, adisintegrating agent, binders, a thickeners, buffers, a sweeteners,flavoring agents or perfuming agents. Additionally, dyestuffs orpigments may be added for identification. Tablets and pills may befurther treated with suitable coating materials known in the art.

Liquid dosage forms for oral administration may be in the form ofpharmaceutically acceptable emulsions, syrups, elixirs, suspensions,slurries and solutions, which may contain an inactive diluent, such aswater. Pharmaceutical formulations may be prepared as liquid suspensionsor solutions using a sterile liquid, such as, but not limited to, anoil, water, an alcohol, and combinations of these. Pharmaceuticallysuitable surfactants, suspending agents, emulsifying agents, may beadded for oral or parenteral administration.

As noted above, suspensions may include oils. Such oils include, but arenot limited to, peanut oil, sesame oil, cottonseed oil, corn oil andolive oil. Suspension preparation may also contain esters of fatty acidssuch as ethyl oleate, isopropyl myristate, fatty acid glycerides andacetylated fatty acid glycerides. Suspension formulations may includealcohols, such as, but not limited to, ethanol, isopropyl alcohol,hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as butnot limited to, poly(ethyleneglycol), petroleum hydrocarbons such asmineral oil and petrolatum; and water may also be used in suspensionformulations.

For intranasal administration (e.g., to deliver compounds to the brain),or administration by inhalation (e.g., to deliver compounds through thelungs), the pharmaceutical formulations may be a solution, a spray, adry powder, or aerosol containing any appropriate solvents andoptionally other compounds such as, but not limited to, stabilizers,antimicrobial agents, antioxidants, pH modifiers, surfactants,bioavailability modifiers and combinations of these. Examples ofintranasal formulations and methods of administration can be found in WO01/41782, WO 00/33813, WO 91/97947, U.S. Pat. No. 6,180,603, and U.S.Pat. No. 5,624,898. A propellant for an aerosol formulation may includecompressed air, nitrogen, carbon dioxide, or a hydrocarbon based lowboiling solvent. The compound or compounds of the instant invention areconveniently delivered in the form of an aerosol spray presentation froma nebulizer or the like.

Injectable dosage forms generally include aqueous suspensions or oilsuspensions which may be prepared using a suitable dispersant or wettingagent and a suspending agent. Injectable forms may be in solution phaseor in the form of a suspension, which is prepared with a solvent ordiluent. Acceptable solvents or vehicles include sterilized water,Ringer's solution, or an isotonic aqueous saline solution.Alternatively, sterile oils may be employed as solvents or suspendingagents. Preferably, the oil or fatty acid is non-volatile, includingnatural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the pharmaceutical formulation may be a powder suitablefor reconstitution with an appropriate solution as described above.Examples of these include, but are not limited to, freeze dried, rotarydried or spray dried powders, amorphous powders, granules, precipitates,or particulates. For injection, the formulations may optionally containstabilizers, pH modifiers, surfactants, bioavailability modifiers andcombinations of these. The compounds may be formulated for parenteraladministration by injection such as by bolus injection or continuousinfusion. A unit dosage form for injection may be in ampoules or inmulti-dose containers.

For rectal administration, the pharmaceutical formulations may be in theform of a suppository, an ointment, an enema, a tablet or a cream forrelease of compound in the intestines, sigmoid flexure and/or rectum.Rectal suppositories are prepared by mixing one or more compounds of theinstant invention, or pharmaceutically acceptable salts or tautomers ofthe compound, with acceptable vehicles, for example, cocoa butter orpolyethylene glycol, which is present in a solid phase at normal storingtemperatures, and present in a liquid phase at those temperaturessuitable to release a drug inside the body, such as in the rectum. Oilsmay also be employed in the preparation of formulations of the softgelatin type and suppositories. Water, saline, aqueous dextrose andrelated sugar solutions, and glycerols may be employed in thepreparation of suspension formulations which may also contain suspendingagents such as pectins, carbomers, methyl cellulose, hydroxypropylcellulose or carboxymethyl cellulose, as well as buffers andpreservatives.

Besides those representative dosage forms described above,pharmaceutically acceptable excipients and carriers are generally knownto those skilled in the art and are thus included in the instantinvention. Such excipients and carriers are described, for example, in“Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991),which is incorporated herein by reference.

The formulations of the invention may be designed for to beshort-acting, fast-releasing, long-acting, and sustained-releasing asdescribed below. Thus, the pharmaceutical formulations may also beformulated for controlled release or for slow release.

The instant compositions may also comprise, for example, micelles orliposomes, or some other encapsulated form, or may be administered in anextended release form to provide a prolonged storage and/or deliveryeffect. Therefore, the pharmaceutical formulations may be compressedinto pellets or cylinders and implanted intramuscularly orsubcutaneously as depot injections or as implants such as stents. Suchimplants may employ known inert materials such as silicones andbiodegradable polymers.

A therapeutically effective dose refers to that amount of the compoundthat results in amelioration of symptoms. Specific dosages may beadjusted depending on conditions of disease, the age, body weight,general health conditions, sex, diet of the subject, dose intervals,administration routes, excretion rate, and combinations of drugs. Any ofthe above dosage forms containing effective amounts are well within thebounds of routine experimentation and therefore, well within the scopeof the instant invention. A therapeutically effective dose may varydepending upon the route of administration and dosage form. Thepreferred compound or compounds of the instant invention is aformulation that exhibits a high therapeutic index. The therapeuticindex is the dose ratio between toxic and therapeutic effects which canbe expressed as the ratio between LD₅₀ and ED₅₀. The LD₅₀ is the doselethal to 50% of the population and the ED₅₀ is the dose therapeuticallyeffective in 50% of the population. The LD₅₀ and ED₅₀ are determined bystandard pharmaceutical procedures in animal cell cultures orexperimental animals.

The present invention also provides methods of enhancing MC4-R activityin a human or non-human animal. The method comprises administering aneffective amount of a compound, or composition, of the instant inventionto said mammal or non-human animal. Effective amounts of the compoundsof the instant invention include those amounts that activate MC4-R whichare detectable, for example, by an assay described below in theillustrative Examples, or any other assay known by those skilled in theart that a detect signal transduction, in a biochemical pathway, throughactivation of G-protein coupled receptors, for example, by measuring anelevated cAMP level as compared to a control model. Accordingly,“activating” means the ability of a compound to initiate a detectablesignal. Effective amounts may also include those amounts which alleviatesymptoms of a MC4-R disorder treatable by activating MC4-R.

An MC4-R disorder, or MC4-R-mediated disease, which may be treated bythose methods provided, include any biological disorder or disease inwhich MC4-R is implicated, or which inhibition of MC4-R potentiates abiochemical pathway that is defective in the disorder or disease state.Examples of such diseases are obesity, erectile disorders,cardiovascular disorders, neuronal injuries or disorders, inflammation,fever, cognitive disorders, type II diabetes, polycystic ovary disease,Syndrome X, complications from obesity and diabetes, and sexual behaviordisorders. In a preferred embodiment, the instant invention providescompounds, compositions, and methods effective for reducing energyintake and body weight; reducing serum insulin and glucose levels;alleviating insulin resistance; and reducing serum levels of free fattyacids. Accordingly, the instant invention is particularly effective intreating those disorders or diseases associated with obesity or type IIdiabetes.

“Treating” within the context of the instant invention, therefore, meansan alleviation of symptoms associated with a disorder or disease, orhalt of further progression or worsening of those symptoms, orprevention or prophylaxis of the disease or disorder. For example,within the context of obesity, successful treatment may include analleviation of symptoms or halting the progression of the disease, asmeasured by reduction in body weight, or a reduction in amount of foodor energy intake. In this same vein, successful treatment of type I ortype II diabetes may include an alleviation of symptoms or halting theprogression of the disease, as measured by a decrease in serum glucoseor insulin levels in, for example, hyperinsulinemic or hyperglycemicpatients.

The present invention, thus generally described, will be understood morereadily by reference to the following examples, which are provided byway of illustration and are not intended to be limiting of the presentinvention.

EXAMPLES

The following abbreviations are used throughout the Examples:

-   DIAD: Diisopropyl azodicarboxylate-   DIEA: Diisopropylethylamine-   DMF: Dimethylformamide-   DMAP: 4-Dimethylaminopyridine-   DMSO: Dimethylsulfoxide-   EDCl: 1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride-   HCl: Hydrochloric acid-   KOH: Potassium hydroxide-   LC: Liquid Chromatography-   MS: Mass Spectroscopy-   NaOH: Sodium Hydroxide-   TFA: Trifluoroacetic acid-   THF: Tetrahydrofuran-   TLC: Thin Layer Chromatography

Example 1

Step 1. General Synthesis of Aryl Azide and Nitroaryl Intermediates.

The 4-azido or 4-nitroarylcarboxylic acid starting materials in ExamplesA-D of Step 1 may also be functionalized as azido ornitropyridylcarboxylic acids. These are commercially available or may beprepared by the following known methods.

To a solution of an amine (1.0 equivalents) and 4-azido or4-nitroarylcarboxylic acid (1.0 equivalents) in THF was added EDCl (1.5equivalents). The mixture was stirred at room temperature for 8-12hours. THF was removed, and the residue was resuspended in ethylacetate, washed with water, dried over sodium sulfate, concentrated, andpurified by silica gel chromatography eluting with ethyl acetate/hexaneor chloroform/methanol.

To a dry THF solution of an acid (0.5 M) and 4-azidoarylamine (1equivalent) was added EDCl (1.5 equivalents). After stirring at roomtemperature for 8 hours, the reaction was concentrated in vacuo. Theresulting mixture was diluted with ethyl acetate and washed with twoportions of water. The organic layer was then isolated and dried oversodium sulfate. The solution was then filtered through a fritted funnel,concentrated, and dried overnight under high vacuum to yield the crudeamidoarylazide product that was used without further purification.

A dry THF solution containing a 4-nitroarylcarboxylic acid (1.5equivalents), an alcohol (1.5 equivalents), DIAD (1.5 equivalents), andPPh₃ (1.5 equivalents) was refluxed. After stirring at reflux for 2hours, the reaction was allowed to cool to room temperature and thenconcentrated in vacuo. The resulting mixture was dissolved in methylenechloride and purified via flash chromatography. The pure fractions werecombined and concentrated in vacuo to yield the pure nitroester product.

To an aryl aldehyde (1 equivalent) dissolved in acetic acid (0.66 M) wasadded nitromethane (3 equivalents) and ammonium acetate (1 equivalent)and the mixture was refluxed overnight. The reaction was cooled to roomtemperature and ethyl acetate was added. The organic phase was washedwith water, NaHCO₃ (saturated aqueous), dried, and evaporated to yield aresidue which was used without further purification.

The crude nitrostyrene product was dissolved in THF (0.2 M), was cooledto 0° C., and was treated with 1.0 M BH₃ in THF (5 equivalents). Thereaction was then heated to reflux overnight. The reaction was cooled to0° C. and quenched with H₂O and then 1 N HCl was added until the pH wasequal to about 2. The reaction was stirred for 30 minutes at roomtemperature and then extracted with ether (3×). The aqueous layer wasmade basic with 5% NaOH solution and then extracted into ether (3×). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, concentrated, and purified by silica gel chromatography. Theamine was then coupled to a 4-azido or 4-nitroarylcarboxylic acid (EDCl,THF) as described in the carboxamide synthesis above.

The resulting carboxamide was suspended in POCl₃, and the mixture washeated at reflux for 1-3 days. The reaction was then cooled to roomtemperature and cautiously poured onto ice. The aqueous mixture waswashed with chloroform, and the organic layer was washed with Na₂CO₃(saturated aqueous). The acidic aqueous phase was cooled at 0° C. andmade basic by addition of solid KOH. The resulting mixture was extractedwith chloroform and the organic layers were combined, dried, andconcentrated in vacuo. The resulting residue was purified on silica gel,eluting with chloroform/methanol.

To a dry THF solution containing an amine (1.0 equivalent, 0.5 M in THF)and 4-fluorobenzenesulfonyl chloride (1.0 equivalent) was addedethyldiisopropylamine (1.1 equivalent). After stirring at roomtemperature for 12 hours, the reaction was concentrated in vacuo. Theresulting mixture was diluted with ethyl acetate and washed with water(3×). The organic layer was then separated and dried over sodiumsulfate. The solution was then filtered through a fritted funnel andconcentrated to yield the crude product.

To a DMSO solution of the crude intermediate (1.0 equivalent, 0.5 M inDMSO) was added sodium azide (10 equivalents) and tetrabutylammoniumchloride (2.3 equivalents). The reaction was fitted with a condenser andheated to 100° C. for 12 hours. The reaction was then cooled to roomtemperature, diluted with ethyl acetate, and washed with water (3×). Theorganic layer was next separated, dried over sodium sulfate, filteredthrough cotton, concentrated, and dissolved in a minimal amount of ethylacetate. The crude mixture was purified via flash chromatography usinghexanes/ethyl acetate. The pure fractions were combined, concentrated,and dried overnight under high vacuum to yield the azide product.Step 2. General Synthesis of Guanidine Products from Aryl Carboxamide,Amide, Ester, and Dihydroisoquinoline Intermediates of Step 1.

To a solution of the corresponding aryl azide (1.0 equivalent) in THFwas added triphenylphosphine (1.0 equivalent) or tributylphosphine (1.0equivalent, for use particularly with pyridylazide compounds) at roomtemperature. After 8 hours, the corresponding isocyanate was added (1.3equivalents), and the solution was heated at 55-80° C. overnight. To themixture was added an amine (1.3 equivalents). After being heated at thesame temperature for 2 hours, THF was removed. The residue wasresuspended in ethyl acetate, washed with water, dried over anhydroussodium sulfate, concentrated, and purified by silica gel chromatography.

B. Preparation from Nitroaryl Compounds

A nitroaryl compound was taken up in ethanol (or methanol) and purgedwith dry nitrogen. To this solution was introduced activated Pd/C (10%w/w, 0.1 equivalent), and the mixture was hydrogenated for about 30minutes or until complete by LC/MS. The mixture was then filteredthrough Celite, concentrated in vacuo, and taken on crude to the nextstep.

To a 0.5 M acetone solution (0° C. ice bath) containing the amine (1equivalent) and sodium carbonate (3 equivalents) was added thiophosgene(3 equivalents) dropwise. After 2 hours at room temperature, thereaction mixture was concentrated in vacuo to remove solvent and excessthiophosgene. The residue was taken up in ethyl acetate and washed withwater, dried with sodium sulfate, and then concentrated in vacuo toyield the isothiocyanate. To a solution of the resulting isothiocyanatein dry THF (0.5 M solution) was added an amine (1.5 equivalents). Afterstirring overnight, the reaction mixture was concentrated in vacuo andthe thiourea product was dissolved in ethyl acetate or methylenechloride and purified via flash chromatography.

To a solution of the thiourea in dry THF (0.1 M) was added EDC (2equivalents) and the solution heated at reflux (−80° C. external temp)for 60 minutes, after which it was cooled to room temperature and thenplaced in an ice bath for 15 minutes with stirring. A methylene chloridesolution containing an amine (2 equivalents) was added and the reactionwas stirred at room temperature. After 20 minutes, the reaction wasdiluted with ethyl acetate and washed with water. The aqueous layer wasback extracted with ethyl acetate and the combined organic layers, afterconcentration in vacuo, was purified by silica gel flash chromatography.

Example 2

The syntheses of additional starting materials that may be used in thegeneral procedures of Example 1 are shown and described below.

4-Azido-N-[2-(4-methoxy-phenyl)-ethyl]-benzamide was cyclized asdescribed in Example 1, Step 1D. To the resulting1-[4-(azadiazomvinyl)phenyl]-7-methoxy-3,4-dihydroisoquinoline (1equivalent) in methanol was added paraformaldehyde (10 equivalents) andNaCNBH₃ (4 equivalents) and the reaction mixture was stirred at roomtemperature overnight. The reaction mixture was filtered through Celite,methanol was removed in vacuo, and the residue was dissolved inchloroform and washed with water. The organic extract was dried overmagnesium sulfate and evaporated in vacuo to give the desiredintermediate as an oil, which was used without further purification.

4-Azido-N-[2-(4-methoxy-phenyl)-ethyl]-benzamide was cyclized asdescribed in Example 1, Step 1D. To a refluxing solution of1-[4-(azadiazomvinyl)-phenyl]-7-methoxy-3,4-dihydroisoquinoline (1equivalent) in dry benzene was added every hour activated MnO₂ (1.2equivalent) (Dean-stark apparatus) for 8 hours, and the mixture wasrefluxed 24 hours. The reaction mixture was filtered through Celite, thefilter cake washed with chloroform, and the filtrate evaporated invacuo. The resulting crude product as purified on silica gel to separatethe starting material, eluting with ethyl acetate/hexane 1:9 to 1:7.

The hydroxymethyl carboxamide starting material was prepared fromO-methyl-L-tyrosine following the procedure described in J. Org. Chem.,65, p. 503 (2000) and the coupling procedure in Example 1, Step 1A. Asolution of the amideN-{(1S)-2-hydroxy-1-[(4-methoxyphenyl)methyl]ethyl}[4-(azadiazomvinyl)phenyl]-carboxamide(1 equivalent) in anhydrous pyridine and acetic anhydride (2equivalents) was stirred at room temperature overnight. The reactionmixture was dissolved in ethyl acetate and washed with 1 M CuSO4. Theorganic extract was dried over magnesium sulfate and evaporated in vacuoto give a solid, which was used without further purification. Theacetate was cyclized (POCl₃) as described in Example 1, step 1D. Thecyclic acetate (1 equivalent) was dissolved in methanol and treated withK₂CO₃ (1 equivalent). After stirring at room temperature for 2 hours,the methanol was removed in vacuo, and the crude product was dissolvedin chloroform and washed with water to yield[1-(4-Azido-phenyl)-7-methoxy-3,4-dihydro-isoquinolin-3-yl]-methanol.

Synthesis of 2-Fluoro-1-iodo-methylbenzene

In a round bottom flask, 2-fluoro-4-methyl aniline (1 g, 7.99 mmol) wassuspended in water (2 mL) and concentrated HCl (2 mL). This solution wasthen cooled in an ice bath with vigorous stirring. To this stirringsolution was added sodium nitrite (662 mg, 9.58 mmol) dissolved in water(2 mL) dropwise over 30 minutes, keeping the temperature below 10° C.The reaction was then stirred for a further 30 minutes. The resultingsolution was then added dropwise to a solution of potassium iodide (1.99g, 11.98 mmol) dissolved in water (2 mL) stirring in an ice bath. Thereaction was then refluxed for 2 hours before being allowed to stir atroom temperature over night. The reaction was then taken up in ethylacetate and washed with HCl (3 N), NaOH (1 M) containing a small portionof sodium metabisuffite. The organic layer was then dried over Na₂SO₄and the solvent removed under reduced pressure to afford 1.46 g (77%yield) of a dark brown oil. This material was then purified via flashchromatography using a hexane running solvent and washed with 1 M HCl(2×), 2 M NaOH, brine and dried over Na₂SO₄ to recover the iodideproduct 829 mg (44% yield) of a colorless oil.

Synthesis of 2-Acetylamino-3-(2-fluoro-4-methyl-phenyl)-acrylic AcidMethyl Ester via the Heck Reaction

A mixture of the aryl iodide (200 mg, 0.817 mmol),methyl-2-acetamidoacrylate (146 mg, 1.017 mmol), Pd(OAc)₂, (23 mg, 0.102mmol), tetrabutylammonium chloride hydrate (283 mg, 1.017 mmol), andsodium hydrogen carbonate (192 mg, 2.288 mmol) was weighed into a 20 mLglass vial, flushed with nitrogen and sealed. The vial was then heatedat 80° C. for 24 hours. The reaction was then cooled to room temperatureand dissolved in methylene chloride. The organic layer was then washedwith brine (3×) and dried over Na₂SO₄. The organic solvent was thenremoved under reduced pressure to yield a dark brown solid. This crudematerial was then purified via flash chromatography using 45% ethylacetate/hexane running solvent to yield the Heck product 129 mg (60%yield) of an off white solid.

Hydrogenation to Form the2(S)-Acetylamino-3-(2-fluoro-4-methyl-phenyl)-propionic Acid MethylEster

In an oven dried Parr hydrogenation vial, the methyl ester above (129mg, 0.51 mmol) was dissolved in anhydrous methanol (3.5 mL) along withthe chiral catalyst (+)-1,2-Bis((2S,5S)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I) trifluoromethanesulfonate (4 mg, 5.5 μmol).The vial was then placed in the Parr pressure reactor, evacuated, andflushed with argon (5×) before evacuating and flooding with hydrogen(5×). The reaction was then allowed to proceed for 3 hours at roomtemperature with stirring. The reaction was then filtered through cottonwool before removing the organic solvent under reduced pressure to yieldthe product 100 mg (78% yield). This material was used without furtherpurification. [M+H]+, 507.4.

Reduction of the Methyl Ester to Form the Acetamide

In an oven dried round bottom flask under nitrogen, LiAlH₄ (22 mg, 0.59mmol) was suspended in anhydrous THF (2 mL) and cooled in an ice bath.To this stirring solution was added dropwise a THF (2 mL) solution ofthe product (50 mg, 0.19 mmol) from the previous step. The reaction wasthen allowed to warm to room temperature and monitored via TLC (45%ethyl acetate/hexane running solvent) until completion withinapproximately 1 hour. The reaction was then cooled in an ice bath anddiluted with water and diethyl ether. To this vigorously stirringsolution was added 2 M NaOH, and the reaction was then allowed to stirfor a further 30 minutes. The aqueous layer was then extracted withdiethyl ether (3×), and the combined organic extracts were dried overNa₂SO₄. The organic layer was then removed under reduced pressure torecover the product alcohol (35 mg, 79% yield) as an off white solid.[MH]+, 451.4.

Hydrolysis of the Acetamide to Form2(S)-amino-3-(2-fluoro-4-methyl-phenyl)-propan-1-ol

In a round bottom flask, the acetamide from the previous step (4.748 g,21.07 mmol) was dissolved in methanol (150 mL) and 2 M NaOH (150 mL) andrefluxed. The reaction was then monitored via TLC using ethyl acetateand ninhydrin stain before it was allowed to cool to room temperatureafter 2 days. The reaction was then extracted with ethyl acetate (3×)and the organic layer dried over Na₂SO₄ before being removed underreduced pressure. This material was then purified via flashchromatography using a 10% methanol/methylene chloride/1% ammoniasolution running solvent to give the amino alcohol 2.871 g (76% yield).

Synthesis of 3-(2,4-Dimethylphenyl)-acrylic Acid Methyl Ester

In an oven dried round bottom flask under nitrogen,2,4-dimethylbenzaldehyde (10 g, 74.52 mmol) and sodium hydride (3.28 g,81.89 mmol) were suspended in anhydrous DMF (100 mL) and stirred in anice bath. To this stirring solution was added dropwise methyldiethyl(phosphonoacetate) (15 mL, 81.98 mmol), and the solution wasallowed to stir for a further 15 minutes before being allowed to warm toroom temperature and proceed for two days. The reaction was then takenup in ethyl acetate and washed with 1 M HCl (2×) and brine. The organiclayer was then dried over sodium sulfate and the solvent removed underreduced pressure to recover the desired product 16.45 g. This materialwas used without further purification.

Hydrogenation to Yield 3-(2,4-Dimethylphenyl)-propionic Acid MethylEster

3-(2,4-dimethylphenyl)-acrylic acid methyl ester (16.45 g, 86.44 mmol)was dissolved in methanol (120 mL) and evacuated (3×) connected to ahydrogenation apparatus. 10% Pd on C (1.0 g) was added to the flaskunder nitrogen, and the reaction was evacuated again. The vigorouslystirring solution was then allowed to proceed under H₂ and monitored viaNMR until the reaction was complete. After two days, the reaction wasfiltered through a Celite pad and concentrated to afford3-(2,4-dimethylphenyl)-propionic acid methyl ester 15.1 g (90% yield).193.1 [M+H]+.

Hydrolysis to Yield 3-(2,4-Dimethylphenyl)-propionic Acid

3-(2,4-dimethylphenyl)-propionic acid methyl ester (15.1 g, 78.54 mmol)was heated to reflux in 2.0 M NaOH (150 mL) overnight. The reaction wascooled, and washed with diethyl ether (2×) and the aqueous layeracidified with 2 N HCl to precipitate the desired3-(2,4-dimethylphenyl)-propionic acid. The precipitate was collected byfiltration and dried under vacuum (9.12 g, 68% yield).

Example 3 Preparation of(3S)-N′-[4-(3,4-Dihydroquinolin-1(2H)-ylcarbonyl)phenyl]-3-methyl-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamideStep 1. Preparation of1-[(4-Azidophenyl)carbonyl]-1,2,3,4-tetrahydroquinoline

A mixture of 1,2,3,4-tetrahydro-quinoline, 4-azidobenzoic acid, and1-[3-(dimethlamino)propyl]-3-ethylcarbodiimide hydrochloride (1:1:1.5)were stirred in THF (0.43 M amine) for 20 hours at room temperature.After decanting and washing any remaining insoluble material with THF,the THF was removed in vacuo. The resulting solid was recrystallizedfrom boiling ethyl acetate.

Step 2. Preparation of(3S)-N′-[4-(3,4-Dihydroquinolin-1(2H)-ylcarbonyl)phenyl]-3-methyl-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

To a solution of 1-[(4-azidophenyl)carbonyl]-1,2,3,4-tetrahydroquinoline(1 equivalent; 0.1 M in anhydrous THF) was added trimethylphosphine (1equivalent; 1 M in THF). After stirring for 10 minutes,(1S,2S,3S,5S)-2,6,6-trimethyl-bicyclo[3.1.1]heptan-3-isocyanate (1.3equivalents) was added. After stirring at 55° C. for 18 hours,(S)-(+)-2-methylpiperazine (1.6 equivalents) was added, and the reactionwas stirred at 55° C. for an additional 2 hours. Volatiles were removedin vacuo and the resulting off-white solid was run through a preparatoryLC. Lyophilization of the pure fractions resulted in a fluffy whitepowder.

Example 4 Preparation of(3S)-3-Methyl-N′-(4-{[7-(methyloxy)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamideStep 1. Preparation of 4-Azido-N{2-[4-(methyloxy)phenyl]ethyl}benzamide

A mixture of 2-(4-methoxy-phenyl)-ethylamine, 4-azidobenzoic acid, and1-[3-(dimethlamino)propyl]-3-ethylcarbodiimide hydrochloride (1:1:1.5)were stirred in THF (0.43 M amine) for 20 hours at room temperature.After decanting and washing any remaining insoluble material with THF,the THF was removed in vacuo. The resulting solid was recrystallizedfrom boiling ethyl acetate.

Step 2. Preparation of2-[(4-Azidophenyl)carbonyl]-7-(methyloxy)-1,2,3,4-tetrahydroisoquinoline

To a mixture of 4-azido-N-{2-[4-(methyloxy)phenyl]ethyl}benzamide andparaformaldahyde (1:1.1) was added formic acid (0.35 M in benzamide).After stirring for 18 hours at 55° C., ethyl acetate was added, and thereaction was washed with saturated aqueous NaHCO₃ and saturated aqueousNaCl. The organic fraction was dried with MgSO₄, followed by removal ofethyl acetate in vacuo. Purification by flash chromatography, elutingwith 30% ethyl acetate in hexanes resulted in a white solid.

Step 3. Preparation of(3S)-3-Methyl-N′-(4-{[7-(methyloxy)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

To a solution of2-[(4-azidophenyl)carbonyl]-7-(methyloxy)-1,2,3,4-tetrahydroisoquinoline(1 equivalent; 0.1 M in anhydrous THF) was added trimethylphosphine (1equivalent; 1 M in THF). After stirring for 10 minutes,(1S,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-isocyanate (1.3equivalents) was added. After stirring at 55° C. for 18 hours,(S)-(+)-2-methylpiperazine (1.6 equivalents) was added, and the reactionwas stirred at 55° C. for an additional 2 hours. Volatiles were removedin vacuo, and the resulting off-white solid was run through apreparatory LC. Lyophilization of the pure fractions resulted in afluffy white powder.

Examples 5-23

The compounds in the following table were prepared using the methodologydescribed in Examples 3 and 4. The starting materials used in thesyntheses are recognizable to one of skill in the art and arecommercially available or may be prepared using known methods. Table ofExamples 5-23 Exam- ple Name MH+ 5(3S)-N′-{4-[(5,7-dimethyl-3,4-dihydroisoquinolin- 542.82(1H)-yl)carbonyl]phenyl}-3-methyl-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 6(3S)-3-methyl-N′-(4-{[6-(methyloxy)-3,4- 544.7dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 7 (3S)-N-[4-(2,3-dihydro-1H-indol-1- 500ylcarbonyl)phenyl]-3-methyl-N′-[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 8(3S)-N′-{5-[(7-bromo-3,4-dihydroisoquinolin-2(1H)- 593.6yl)carbonyl]pyridin-2-yl}-3-methyl-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 9(3S)-N′-{5-[(7-chloro-3,4-dihydroisoquinolin-2(1H)- 549.2yl)carbonyl]pyridin-2-yl}-3-methyl-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 10(3S)-N′-{5-[(7-fluoro-3,4-dihydroisoquinolin-2(1H)- 533.3yl)carbonyl]pyridin-2-yl}-3-methyl-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 11(3S)-N-cyctoheptyl-3-methyl-N′-(4-{[7-(methyloxy)- 504.23,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)piperazine-1-carboximidamide 12(3S)-3-methyl-N-(4-methylcyclohexyl)-N′-(4-{[6- 504.5(methyloxy)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)piperazine-1-carboximidamide 13(3S)-N′-(4-{[6,7-bis(methyloxy)-3,4- 574.5dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-3-methyl-N-[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 14(3S)-3-methyl-N-(4-methylcyclohexyl)-N′-(4-{[7- 504.5(methyloxy)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)piperazine-1-carboximidamide 15(3S)-N-cycloheptyl-3-methyl-N′-(4-{[6-(methyloxy)- 504.63,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)piperazine-1-carboximidamide 16(3S)-N′-{4-[(5,7-dimethyl-3,4-dihydroisoquinolin- 502.52(1H)-yl)carbonyl]phenyl}-3-methyl-N-(4-methylcyclohexyl)piperazine-1-carboximidamide 17(3S)-N-cycloheptyl-N′-{4-[(5,7-dimethyl-3,4- 502.5dihydroisoquinolin-2(1H)-yl)carbonyl]phenyl}-3-methylpiperazine-1-carboximidamide 18(3S)-N′-(4-{[6,7-bis(methyloxy)-3,4- 534.5dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-cycloheptyl-3-methylpiperazine-1-carboximidamide 19(3S)-N′-(4-{[6,7-bis(methyloxy)-3,4- 534.3dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-3-methyl-N-(4-methylcyclohexyl)piperazine-1- carboximidamide 20(3S)-N-{4-[(7-bromo-3,4-dihydroisoquinolin-2(1H)- 592.2yl)carbonyl]phenyl}-3-methyl-N′-[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 21(3S)-N-{4-[(7-chloro-3,4-dihydroisoquinolin-2(1H)- 548.2yl)carbonyl]phenyl}-3-methyl-N′-[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 22(3S)-N-{4-[(7-fluoro-3,4-dihydroisoquinolin-2(1H)- 532yl)carbonyl]phenyl}-3-methyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 23(3S)-3-methyl-N-(5-{[7-(methyloxy)-3,4- 545dihydroisoquinolin-2(1H)-yl]carbonyl}pyridin-2-yl)-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

Example 24 Preparation of(3S)-3-methyl-N-(4-{[7-(methyloxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl]carbonyl}phenyl)-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

Step 1.

2-(3-methoxy-phenyl)-ethylamine (1 equivalent) was dissolved inanhydrous methylene chloride (0.88 M) in a three necked round bottomflask under N₂ and stirred in an ice bath. Tosyl chloride (1.25equivalent) was then dissolved in anhydrous methylene chloride under N₂and added to this stirring solution over 10 minutes (Caution! This is anexothermic reaction). A precipitate formed, DIEA (1.2 equivalent) wasthen added, and the reaction was stirred at room temperature overnight.The reaction was then washed with 10% citric acid, 10% sodium carbonate,and brine before being dried over sodium sulfate. The organic solventwas then removed under reduced pressure to provide a brown oil. Thiscrude material was then purified via flash chromatography using 100%methylene chloride running solvent to recover the product sulfonamide.(MH⁺) 306.1.

Step 2.

The sulfonamide (1 equivalent) produced in Step 1 was dissolved inacetone and stirred in a round bottom flask with K₂CO₃ (6.9equivalents). The mixture was warmed to 78° C. and refluxed. Ethylbromoacetate (1.5 equivalents) was then added, and the reaction wasallowed to proceed overnight. The K₂CO₃ was then filtered off, and thesolvent was removed under reduced pressure. To this colorless oil wasadded NaOH (4.4 equivalents) dissolved in 50% ethanol (0.4 M). Themixture was then warmed to reflux at 90° C. and allowed to proceedovernight. The ethanol was then removed under reduced pressure. Theresidual oil was then washed with water and extracted with diethylether. The aqueous layer was then acidified with concentrated HCl andextracted with diethyl ether (2×). The organic layers were then combinedand extracted with sodium carbonate (2×). The aqueous layers were thencombined and acidified with concentrated HCl and extracted with diethylether (2×). The organic layers were then combined and dried over sodiumsulfate. The organic solvent was then removed under reduced pressure.The resulting material was then recrystallized from ethylacetate/petroleum spirit to recover the alkylated product[[2-(3-methoxy-phenyl)-ethyl]-(toluene-4-sulfonyl)-amino]-acetic acid.(MH+) 363.9.

Step 3.

[[2-(3-Methoxy-phenyl)-ethyl]-(toluene-4-sulfonyl)-amino]-acetic acid (1equivalent) was dissolved in anhydrous methylene chloride (0.13 M) andadded to a stirring solution of P₂O₅ (5 equivalents) suspended inanhydrous methylene chloride (0.13 M) at 0° C. under nitrogen. Thereaction was then allowed to proceed at room temperature for two daysbefore being worked up. The reaction mixture was then diluted with 3%NaOH and extracted with methylene chloride. The organic layers were thencombined and dried over sodium sulfate, and the solvent was removedunder reduced pressure to recover the cyclized product8-methoxy-3-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-benzo[d]azepin-1-one.The regio-isomer (ortho cyclized product) is formed in this reaction.The resulting material was purified via flash chromatography using 20%acetone/petroleum spirit running solvent. Two separate fractions of thedesired isomeric pure8-methoxy-3-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-benzo[d]azepin-1-onewere recovered. These two fractions were treated separately for the nextreaction. (MH+) 346.1.

Step 4.

The ketone product from Step 3 was dissolved in neat TFA and stirredunder nitrogen. To this stirring solution was added triethyl silane (2.2equivalents), and the reaction was allowed to proceed overnight at roomtemperature. Aqueous sodium carbonate was then added, and the solutionwas extracted with ether (2×). The ether layers were then combined anddried over sodium sulfate, and the solvent was removed under reducedpressure to recover an orange oil. The crude material from the tworeactions was then combined and purified via flash chromatography using20% acetone/1% ammonia solution/petroleum spirit to give7-methoxy-3-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.(MH+) 178.0.

Step 5.

Gaseous ammonia was first condensed into an oven dried three neckedround bottom flask in a dry ice acetone bath under N₂. Sodium metal wasthen added to this vigorously stirring liquid ammonia to form sodiumamide. The solution should hold a deep blue color to confirm that theliquid ammonia is anhydrous. The sulfonamide (1 equivalent) from Step 4was then dissolved in THF (0.1 M) in an oven dried round bottom flaskconnected to a dry ice condenser. The anhydrous liquid ammonia was thendistilled across into the round bottom flask containing the sulfonamidewith vigorous stirring via the dry ice condenser connected in a seriesunder a steady stream of N₂. Once the distillation had finished, thecondenser and round bottom flask containing the sulfonamide wasisolated. Sodium metal (2.1 equivalents) was then added until thesolution again became a deep blue color. The reaction was stirred for afurther 30 minutes before being quenched with NH₄Cl (9.3 equivalents).The reaction was then extracted with diethyl ether and dried over sodiumsulfate, and the solvent was removed under reduced pressure to give theproduct amine as a yellow oil. (MH+) 353.3.

Step 6.

7-Methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1 equivalent) wasdissolved in THF (0.1 M) along with azidobenzoic acid (1.5 equivalents),EDCl (1.5 equivalents), DMAP (0.18 equivalents), and DIEA (1.5equivalents). The reaction was stirred at room temperature overnight.The reaction was then washed with 10% citric acid, saturated sodiumcarbonate, and brine. The organic layer was then dried over sodiumsulfate, and the organic solvent was removed under reduced pressure. Thematerial was then purified via flash chromatography using 8% acetone/1%ammonia solution/petroleum spirit running solvent to give(4-azido-phenyl)-(7-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-methanone.(MH+) 323.2.

Step 7.

(3S)-3-methyl-N-(4-{[7-(methyloxy)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl]carbonyl}phenyl)-N′-[(1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamidewas prepared using the product of Step 6 and following the procedure inExample 3. (MH+) 558.8.

Examples 25-45

The compounds in the following table were prepared using the methodologydescribed in Examples 1 and 2. The starting materials used in thesyntheses are recognizable to one of skill in the art and arecommercially available or may be prepared using known methods. Table ofExamples 25-45 Example Name MH+ 25(3S)-3-methyl-N-{4-[7-(methyloxy)-3,4- 514dihydroisoquinolin-1-yl]phenyl}-N′-[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 26(3S)-3-methyl-N-[4-(7-methyl-3,4- 498dihydroisoquinolin-1-yl)phenyl]-N′-[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 27(3S)-3-methyl-N-{4-[7-(methyloxy)-1,2,3,4- 516tetrahydroisoquinolin-1-yl]phenyl}-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 28 (3S)-N-{4-[6,7-bis(methyloxy)-3,4-544 dihydroisoquinolin-1-yl]phenyl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 29(3S)-3-methyl-N-{4-[6-(methyloxy)-3,4- 514dihydroisoquinolin-1-yl]phenyl}-N′-[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 30(3S)-3-methyl-N-{4-[2-methyl-7-(methyloxy)-1,2,3,4- 530tetrahydroisoquinolin-1-yl]phenyl}-N′-[(1S,2S,3R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 31(3S)-N-[4-(3,4-dihydrobenzo[h]isoquinolin-1- 534yl)phenyl]-3-methyl-N′-[(1S,2S,3R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 32(3S)-3-methyl-N-(4-{7-[(1-methylethyl)oxy]-3,4- 542dihydroisoquinolin-1-yl}phenyl)-N′-[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 33(3S)-3-methyl-N-{4-[7-(methyloxy)isoquinolin-1- 512yl]phenyl}-N′-[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 34(3S)-3-methyl-N-{4-[7-(1-methylethyl)-3,4- 526dihydroisoquinolin-1-yl]phenyl}-N′-[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 35(3S)-N-{4-[7-(ethyloxy)-3,4-dihydroisoquinolin-1- 528yl]phenyl}-3-methyl-N′-[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 36(3S)-N-{4-[(3S)-3-(hydroxymethyl)-7-(methyloxy)- 5443,4-dihydroisoquinolin-1-yl]phenyl}-3-methyl-N′-[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 37(3S)-3-methyl-N-{5-[7-(methyloxy)-3,4- 515dihydroisoquinolin-1-yl]pyridin-2-yl}-N′-[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 38(3S)-N-{5-[7-(ethyloxy)-3,4-dihydroisoquinolin-1- 529yl]pyridin-2-yl}-3-methyl-N′-[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 39(3S)-N-{4-[7-(butyloxy)-3,4-dihydroisoquinolin-1- 556yl]phenyl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 40(3R,5S)-N-{4-[7-(butyloxy)-3,4-dihydroisoquinolin-1- 570yl]phenyl}-3,5-dimethyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 41(3S)-N-{5-[7-(1,1-dimethylethyl)-3,4- 542dihydroisoquinolin-1-yl]pyridin-2-yl}-3-methyl-N′-[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 42(3R,5S)-N-{5-[7-(ethyloxy)-3,4-dihydroisoquinolin-1- 543yl]pyridin-2-yl}-3,5-dimethyl-N′-[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 43(3R,5S)-3,5-dimethyl-N-{5-[7-(1-methylethyl)-3,4- 541dihydroisoquinolin-1-yl]pyridin-2-yl}-N′-[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl](piperazine-1-carboximidamide 44(3S)-N-{5-[7-(1,1-dimethylethyl)-3,4- 541dihydroisoquinolin-1-yl]pyridin-2-yl}-3-methyl-N′-[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 45(3S,5S)-N-{5-[7-(ethyloxy)-3,4-dihydroisoquinolin-1- 544yl]pyridin-2-yl}-3,5-dimethyl-N′-[(1S,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide

Examples 46-76

The compounds in the following table were prepared using the methodologydescribed in Examples 1 and 2. The starting materials used in thesyntheses are recognizable to one of skill in the art and arecommercially available or may be prepared using known methods. Table ofExamples 46-76 Ex- am- ple Name MH+ 46 2-(2,4-dichlorophenyl)ethyl4-[((Z)-[(3S)-3- 571.2 methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzoate 472-(2,4-dichlorophenyl)ethyl 4-[((Z)-[(3R,5S)-3,5- 585.2dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]benzoate 482-(2,4-dichlorophenyl)ethyl 4-[((Z)-[(3S)-3- 585.1methylpiperazin-1-yl]{[4-(trifluoromethyl)cyclohexyl]imino}methyl)amino]benzoate 494-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- 413.2yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]benzoic acid 504-chloro-N-{4-[((E)-[(3S)-3-methylpiperazin-1- 551.3yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-D- phenylalaninamide 51 ethyl4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- 441.3yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]benzoate 523-[2-fluoro-4-(methyloxy)phenyl]-N-{4-[((Z)-[(3S)-3- 550.3methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}propanamide53 3-(2,4-dimethylphenyl)-N-{4-[((Z)-[(3S)-3- 530.3methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}propanamide54 3-(2-fluoro-4-methylphenyl)-N-{4-[((Z)-[(3S)-3- 534.3methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}propanamide55 2,4-dichloro-N-{4-[((Z)-[(3S)-3-methylpiperazin-1- 585.2yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-L- phenylalaninamide 562,4-dichloro-N-{4-[((Z)-[(3S)-3-methylpiperazin-1- 585.2yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-D- phenylalaninamide 572,4-dichloro-N-{4-[((Z)-[(3R,5S)-3,5- 599.3dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-D-phenylalaninamide 58N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- 546.3yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-[4- (methyloxy)phenyl]propanamide 59N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- 564.3yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-[2-fluoro-4-(methyloxy)phenyl]propanamide 60N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- 548.3yl]{[((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-(2-fluoro-4- methylphenyl)propanamide61 3-[2,4-bis(methyloxy)phenyl]-N-{4-[((Z)-[(3R,5S)- 576.33,5-dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}propanamide62 N-acetyl-N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin- 605.41-yl]{[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-2-fluoro-4-methyl-D- phenylalaninamide 63N-acetyl-N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin- 621.31-yl]{[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-2-fluoro-O-methyl-D- tyrosinamide 64N-acetyl-N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin- 621.31-yl]{[(1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-2-fluoro-O-methyl-L-tyrosinamide 65N²-acetyl-3-(1,3-benzodioxol-4-yl)-N¹-{4-[((Z)- 617.3[(3R,5S)-3,5-dimethylpiperazin-1-yl]-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-D-alaninamide 66N-acetyl-N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin- 609.31-yl]{[(1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-2,4-difluoro-D-phenylalaninamide 67N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- 603.3yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-2-fluoro-O-methyl- D-tyrosinamide 68N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- 563.4yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-2-fluoro-4-methyl- D-phenylalaninamide69 N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- 579.3yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-2-fluoro-O-methyl- D-tyrosinamide 70N-{4-[((Z)-[(3S,5S)-3,5-dimethylpiperazin-1- 548.3yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-(2-fluoro-4- methylphenyl)propanamide71 N-{4-[((Z)-[(3S,5S)-3,5-dimethylpiperazin-1- 564.3yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-[2-fluoro-4-(methyloxy)phenyl]propanamide 72 (3S)-N-[4-({[2-(2,4- 566.1dichlorophenyl)ethyl]amino}sulfonyl)phenyl]-3-methyl-N′-(2-methylcyclohexyl)piperazine-1- carboximidamide 73(3S)-N′-cyclohexyl-N-[4-({[2-(2,4- 552.1dichlorophenyl)ethyl]amino}sulfonyl)phenyl]-3-methylpiperazine-1-carboximidamide 74 (3S)-N-[4-({[2-(2,4- 566dichlorophenyl)ethyl]amino}sulfonyl)phenyl]-3-methyl-N′-(4-methylcyclohexyl)piperazine-1- carboximidamide 75(3S)-N-[4-({[2-(2,4-dichlorophenyl)ethyl]amino}- —sulfonyl)phenyl]-3-methyl-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 76(3S)-N-[4-({[2-(2,4-dichlorophenyl)ethyl]amino}- —sulfonyl)phenyl]-3-methyl-N′-spiro[2.5]oct-4-ylpiperazine-1-carboximidamide

Examples 77-135

The compounds in the following table were prepared using the methodologydescribed in Examples 1 and 2. The starting materials used in thesyntheses are recognizable to one of skill in the art and arecommercially available or may be prepared using known methods. Thesecompounds were named using using ACD Name version 5.07 software (Nov.14, 2001) available from Advanced Chemistry Development, Inc. Table ofExamples 77-135 Ex- am- ple Name MH+ 77(2S)-N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- 684.9yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-[2-fluoro-4- (methyloxy)phenyl]-2-{[(phenylmethyl)oxy]methyl}propanamide 78(2R)-2-amino-3-(2,4-dichlorophenyl)-N-{4-[((Z)- 586.6[(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}propanamide79 (2S)-2-amino-3-(2,4-dichlorophenyl)-N-{4-[((Z)- 586.6[(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}propanamide80 3-(4-bromo-2-fluorophenyl)-N-{4-[((Z)-[(3S)-3- 599.6methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}propanamide81 (2R)-2-amino-3-(2,4-dichlorophenyl)-N-{4-[((Z)- 586.6[(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}propanamide82 3-[2,4-bis(methyloxy)phenyl]-N-{4-[((Z)-[(3S)-3- 562.8methylpiperazin-1-yl]{[(1S,2S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}propanamide 83 1,1-dimethylethyl(1R)-1-[(4-chlorophenyl)methyl]-2- 652.3({4-[((E)-[(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}amino)-2- oxoethylcarbamate 843-(4-bromo-2-fluorophenyl)-N-{4-[((E)-[(3R,5S)-3,5- 613.6dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}propanamide85 3-(4-bromo-2-fluorophenyl)-N-{4-[((E)-[(3R,5S)-3,5- 613.6dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}propanamide86 (2R)-2-amino-3-(4-chlorophenyl)-N-{4-[((E)-[(3S)-3- 552.2methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}propanamide87 (2R)-2-amino-3-(2,4-dichlorophenyl)-N-{4-[((Z)- 586.6[(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}propanamide88 3-(2,4-dichlorophenyl)-N-{4-[((E)-[(3S)-3- 571.6methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}propanamide89 3-(2,4-difluorophenyl)-N-{4-[((E)-[(3S)-3- 538.7methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}propanamide90 3-(2,4-dimethylphenyl)-N-{4-[((E)-[(3R,5S)-3,5- 544.8dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}propanamide91 3-(2,4-dimethylphenyl)-N-{4-[((Z)-[(3S)-3- 530.8methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}propanamide92 3-(2,4-dichlorophenyl)-N-[4-({(E)-[(4- 531.5methylcyclohexyl)imino][(3S)-3-methylpiperazin-1-yl]methyl}amino)phenyl]propanamide 93(2R)-2-amino-3-(2,4-dichlorophenyl)-N-{4-[((Z)- 586.6[(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}propanamide94 (2R)-2-amino-3-(2,4-dichlorophenyl)-N-{4-[((Z)- 586.6[(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}propanamide95 N-[4-({(Z)-(cyclohexylimino)[(3S)-3-methylpiperazin- 517.51-yl]methyl}amino)phenyl]-3-(2,4- dichlorophenyl)propanamide 96(3R)-3-amino-N-{4-[((Z)-[(3S)-3-methylpiperazin-1- 517.7yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3- phenylpropanamide 97(2R)-2-amino-3-(2,4-dichlorophenyl)-N-{4-[((Z)- 600.6[(3R,5S)-3,5-dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}propanamide 98(3R)-N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- 543.8yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxamide 99(2R)-2-(acetylamino)-N-{4-[((Z)-[(3R,5S)-3,5- 605.8dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-(2-fluoro-4- methylphenyl)propanamide100 (2S)-2-amino-3-(2,4-dichlorophenyl)-N-{4-[((Z)- 600.6[(3R,5S)-3,5-dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}propanamide 101(2R)-2-(acetylamino)-N-{4-[((Z)-[(3R,5S)-3,5- 621.8dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-[2-fluoro-4-(methyloxy)phenyl]propanamide 102(2S)-2-(acetylamino)-N-{4-[((Z)-[(3R,5S)-3,5- 621.8dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-[2-fluoro-4-(methyloxy)phenyl]propanamide 103(2R)-2-(acetylamino)-3-(1,3-benzodioxol-4-yl)-N-{4- 617.8[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}propanamide 104(2R)-2-(acetylamino)-3-(2,4-difluorophenyl)-N-{4- 609.8[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}propanamide 105(2R)-2-(acetylamino)-N-{4-[((Z)-[(3R,5S)-3,5- 603.8dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}-3-[3-(methyloxy)phenyl]propanamide 106 (2R)-2-amino-N-{4-[((Z)-[(3R,5S)-3,5-563.8 dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-(2-fluoro-4- methylphenyl)propanamide107 (2R)-2-amino-N-{4-[((Z)-[(3R,5S)-3,5- 579.8dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-[2-fluoro-4-(methyloxy)phenyl]propanamide 108(2R)-2-(acetylamino)-3-(1,3-benzodioxol-5-yl)-N-{4- 617.8[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}propanamide 109(2S)-2-(acetylamino)-3-(1,3-benzodioxol-4-yl)-N-{4- 603.8[((Z)-[(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}propanamide 110(2S)-2-(acetylamino)-N-{4-[((Z)-[(3R,5S)-3,5- 603.8dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}-3-[3-(methyloxy)phenyl]propanamide 111(2S)-2-(acetylamino)-3-(2,4-difluorophenyl)-N-{4- 609.8[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}propanamide 112 1,1-dimethylethyl(1R)-2-({4-[((Z)-[(3R,5S)-3,5- 681.9dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}amino)-1-(naphthalen-1-ylmethyl)-2-oxoethylcarbamate 113 1,1-dimethylethyl(1R)-2-({4-[((Z)-[(3R,5S)-3,5- 681.9dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}amino)-1-(naphthalen-2-ylmethyl)-2-oxoethylcarbamate 114(2R)-2-amino-N-{4-[((Z)-[(3R,5S)-3,5- 581.8dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-naphthalen-1- ylpropanamide 115(2R)-2-amino-N-{4-[((Z)-[(3R,5S)-3,5- 581.8dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-naphthalen-2- ylpropanamide 1163-[2-fluoro-4-(methyloxy)phenyl]-N-{4-[((Z)-[(3S)-3- 564.6methylpiperazin-1-yl]{[4-(trifluoromethyl)cyclohexyl]imino}methyl)amino]phenyl} propanamide 117(2R)-2-amino-3-[2-fluoro-4-(methyloxy)phenyl]-N-{4- 565.7[((Z)-[(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}propanamide 118(2R)-2-(acetylamino)-3-(4-bromo-2-fluorophenyl)-N- 670.7{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}propanamide 119(3R)-N-[(1R)-1-[(4-chlorophenyl)methyl]-2-({4-[((Z)- 725.4[(3R,5S)-3,5-dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}amino)-2-oxoethyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide 120(3R)-N-[(1R)-1-[(4-chlorophenyl)methyl]-2-({4-[((Z)- 711.4[(3S)-3-methylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}amino)-2-oxoethyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide 121(2S)-N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- 684.9yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-[2-fluoro-4- (methyloxy)phenyl]-2-{[(phenylmethyl)oxy]methyl}propanamide 122(2S)-N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- 594.8yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-[2-fluoro-4-(methyloxy)phenyl]-2-(hydroxymethyl)propanamide 123(2R)-2-(acetylamino)-3-(2,4-dimethylphenyl)-N-{4- 601.8[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}propanamide 124 phenylmethyl(1R)-2-({4-[((Z)-[(3S,5S)-3,5- 727.9dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}amino)-1-{[2-fluoro-4-(methyloxy)phenyl]methyl}-2- oxoethyl(methyl)carbamate 125(2R)-2-(acetylamino)-3-(2,4-dimethylphenyl)-N-{4- 601.8[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}propanamide 126(2S)-3-(2,4-dimethylphenyl)-N-{4-[((Z)-[(3R,5S)-3,5- 574.8dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}-2-(hydroxymethyl)propanamide 127(2S)-N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- 578.8yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-(4-fluoro-2-methylphenyl)-2-(hydroxymethyl)propanamide 128(2S)-N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- 668.9yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-(2-fluoro-4- methylphenyl)-2-{[(phenylmethyl)oxy]methyl}propanamide 129(2S)-3-(2,4-dimethylphenyl)-N-{4-[((Z)-[(3R,5S)-3,5- 664.9dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)amino]phenyl}-2-{[(phenylmethyl)oxy]methyl}propanamide 130(2S)-N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- 578.8yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-(2-fluoro-4-methylphenyl)-2-(hydroxymethyl)propanamide 131(2R)-N-{4-[((Z)-[(3S,5S)-3,5-dimethylpiperazin-1- 593.8yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-[2-fluoro-4-(methyloxy)phenyl]-2-(methylamino)propanamide 132(2S)-3-{[(3-bromophenyl)methyl]oxy}-N-{4-[((Z)- 763.8[(3R,5S)-3,5-dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-2-{[2-fluoro-4-(methyloxy)phenyl]methyl}propanamide 133(2S)-N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- 698.9yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-[2-fluoro-4-(methyloxy)phenyl]-2-({[(4- methylphenyl)methyl]oxy}methyl)propanamide134 (2S)-N-{4-[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1- 702.9yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-3-[2-fluoro-4-(methyloxy)phenyl]-2-({[(4- fluorophenyl)methyl]oxy}methyl)propanamide135 (2S)-3-{[(4-chloro-2-fluorophenyl)methyl]oxy}-N-{4- 737.3[((Z)-[(3R,5S)-3,5-dimethylpiperazin-1-yl]{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)amino]phenyl}-2-{[2-fluoro-4-(methyloxy)phenyl]methyl}propanamide

EC₅₀ values of test compounds were determined by treating cellsexpressing MC4-R with test compound and lysing the cells and measuringintercellular cAMP concentration with an Amersham-Pharmacia RPA-559 cAMPScintillation Proximity Assay (SPA) kit. The compounds described abovewere synthesized and tested according to this assay. Each of the namedcompounds of Examples 3-135 were found or will be found to exhibit MC4-Ragonist activity and thus is useful in treating MC4-R mediatedconditions. Additionally, Examples 3-95,97,99-102, 106, 107, 121, 126,128-130, and 132-135 exhibited −log EC₅₀ values above about 3. For thesereasons, each of the exemplary compounds are individually preferred andare preferred as a group. Furthermore, the groups corresponding to R¹through R¹⁹, R^(1′) through R^(4′), Q, W, X, Y, and Z, and the values ofm and n for each of the named compounds of Examples 3-135 are alsopreferred. Nomenclature for these compounds was provided usingACD/namebatch version 4.53 software available from Advanced ChemistryDevelopment, Inc. and ACD Name version 5.07 software (Nov. 14, 2001)available from Advanced Chemistry Development, Inc. Some of the startingmaterials were named using standard IUPAC nomenclature and ChemDrawAutoNom version 2.1. Example compounds 3-135 are illustrative and shouldnot be construed as limiting of the instant invention.

In Vivo Studies of MC4-R Agonists on Energy Intake, Body Weight,Hyperinsulinemia, and Glucose Levels

In vivo studies are conducted to observe the effect of MC-R4 agonists onenergy intake, body weight, hyperinsulinemia, and glucose levels. Allstudies are conducted with male 9-10 week old ob/ob mice which displayearly onset of obesity, insulin resistance and diabetes due to leptindeficiency. Mice are acclimated in the facility for 1 week beforestudies and are caged individually. Vehicle-treated (control) and drugtreated mice studies are always run in parallel. In multi-day studies,mice (8-15 per group) are monitored for baseline body weight, fastinglevels of glucose, insulin, blood lipids and energy expenditure and theninjected twice daily (9 a.m. and 5 p.m.) with 3 mg/kg of a MC4-R agonistof the present invention for 4 weeks. Body weight as well as food andwater intake are monitored daily. Animals are fasted overnight formeasurements of fasting levels of glucose, insulin, and lipids once aweek until the end of the study. Energy expenditure (resting metabolicrate, i.e., O₂ consumption and CO₂ production) are monitored in airtight chambers at the end of the study on fed animals. O₂ consumptionand CO₂ production are measured using Oxymax systems (ColumbusInstruments). Oral glucose tolerance test (OGTT—a routine test fordiabetes and glucose intolerance) is performed on overnight fasted miceat the end of the study. Blood glucose and oral glucose tolerance aremeasured using a glucose monitor (Onetouch sold by Lifescan). Free fattyacids are measured using an non-esterified free fatty acids enzymaticassay (Waco Chemicals). Serum Insulin levels are measured by immunoassay(Alpco).

Results

The effect of the compounds of the present invention on food intake isdetermined by measuring grams/mouse/day throughout a 4 week study. Foodis monitored every morning. Cumulative food intake represents the totalamount of grams the mice consume during the study. A significantreduction in food intake is demonstrated in those mice treated IP withthe compounds of the present invention.

The effect of the compounds of the present invention on body weight isdetermined by measuring grams/mouse throughout a 4 week study. Mice areweighed every morning. A significant body weight reduction isdemonstrated in those mice treated IP with the compounds of the presentinvention.

The effect of the compounds of the present invention on blood glucoselevels is determined by measuring blood glucose levels as represented asmg of glucose/dL of blood. Mice are fasted overnight and glucose levelsare measured the following morning. Vehicle treated mice show anincrease in blood glucose consistent with the rapid progression ofdiabetes in this mouse strain whereas, diabetes is slowed downconsiderably in drug treated mice. A significant reduction in fastingglucose levels is demonstrated in those mice treated IP with thecompounds of this invention.

The effect of the compounds of the present invention on glucose levelsduring oral glucose tolerance test (OGTT) is determined by measuringblood glucose in overnight fasted mice. Blood glucose is represented asmg of glucose/dL of blood. Glucose levels are measured the followingmorning. Orally administered glucose quickly elevates blood glucose,similar to a meal, and the response to this exogenous glucose gives ameasure of how well the body regulated glucose homeostasis. Vehicletreated mice show an elevated response to glucose consistent with theirdiabetic state, whereas drug treated mice show a very much improvedglucose disposal.

The effect of the compounds of the present invention on free fatty acid(FFA) levels is determined by measuring mmoles of FFA/L of serum. Miceare fasted overnight and free fatty acid levels are measured thefollowing morning. Vehicle treated mice show elevated levels of FFAthroughout the study consistent with their obese state, whereas the drugtreated mice diabetes show a dramatic decrease.

The effect of the compounds of the present invention on serum insulinlevels is determined by measuring serum insulin levels one hour aftersingle IP dosing of 1 and 3 mg/kg in overnight fasted ob/ob mice. Seruminsulin levels are represented as ng of insulin/mL of serum. Drugtreated mice show a dose dependent decrease relative to vehicle.

It is understood that the invention is not limited to the embodimentsspecifically set forth herein for illustration, but embraces all suchforms thereof as would be understood by one of skill in the art and comewithin the scope of the following claims.

1. A compound of formula A¹-A²-A³-A⁴ wherein A¹ is a group of formulaIIA or IIB;

R^(1′) is selected from the group consisting of H, and substituted andunsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups;R^(2′) is selected from the group consisting of substituted andunsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups; orR^(1′) and R^(2′), together with the nitrogen to which they are bound,form a substituted or unsubstituted heterocyclyl or heteroaryl group;R^(3′) is selected from the group consisting of substituted andunsubstituted aryl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl,heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, andcycloalkylalkyl groups; R^(4′) is selected from the group consisting ofH, and substituted and unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heteroaryl,heterocyclyl, arylalkyl, and heteroarylalkyl groups; A² is selected fromthe group consisting of substituted and unsubstituted aryl groups andsubstituted and unsubstituted heteroaryl groups; A³ is a covalent bondsuch that A² is directly bonded to A⁴, or A³ is a linking group selectedfrom the group consisting of O, S, —NR^(a)—, —C(═O)—, —C(═O)O—,—NR^(a)C(═O)—, —SO₂NR^(a)—, —C(═S)—, —C(═O)S—, —P(═O)R^(b)—, —SO₂—, and—S(═O)—, wherein if A³ is a linking group, then it is bonded to A² andA⁴ in a configuration selected from the group consisting of A²-O-A⁴,A²-S-A⁴, A²-NR^(a)-A⁴, A²-C(═O)-A⁴, A²-C(═O)O-A⁴, A⁴-C(═O)O-A²,A²-NR^(a)C(═O)-A⁴, A⁴-NR^(a)C(═O)-A², A²-SO₂NR^(a)-A⁴, A⁴-SO₂NR^(a)-A²,A²-C(═S)-A⁴, A²-(C═O)S-A⁴, A⁴-(C═O)S-A², A²-(P═O)R^(b)-A⁴, A²-SO₂-A⁴,and A²-S(═O)-A⁴ provided that if A³ is a linking group with theconfiguration A⁴-NR^(a)C(═O)-A², then A² is not a substituted orunsubstituted phenyl group and is not a substituted or unsubstituted6-membered N-containing heteroaryl group; A⁴ is selected from the groupconsisting of substituted and unsubstituted arylalkyl, heteroarylalkyl,aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl,cycloalkylalkyl, alkenyl, alkynyl, and alkyl groups; R^(a) is selectedfrom the group consisting of H, and substituted and unsubstitutedarylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, and alkyl groups;R^(b) is selected from the group consisting of substituted andunsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl,alkynyl, and alkyl groups; and prodrugs thereof, pharmaceuticallyacceptable salts thereof, stereoisomers thereof, tautomers thereof,hydrates thereof, hydrides thereof, or solvates thereof.
 2. The compoundof claim 1, wherein A² is selected from the group consisting ofsubstituted and unsubstituted phenyl groups and substituted andunsubstituted pyridyl groups.
 3. The compound of claim 1, wherein A³ isa linking group bonded to A² and A⁴ in a configuration selected from thegroup consisting of A²-NR^(a)-A⁴, A²-C(═O)-A⁴, A²-C(═O)O-A⁴,A⁴-C(═O)O-A², A²-NHC(═O)-A⁴, A²-SO₂NH-A⁴, and A²-SO₂-A⁴.
 4. The compoundof claim 1, wherein R^(3′) is selected from the group consisting ofsubstituted and unsubstituted cycloalkyl, polycyclic cycloalkyl,alkenyl, alkyl, and aryl groups.
 5. The compound of claim 1, whereinR^(3′) is selected from the group consisting of substituted andunsubstituted cyclohexyl, 2-alkylcyclohexyl, 2,2-dialkylcyclohexyl,2,3-dialkylcyclohexyl, 2,4-dialkylcyclohexyl, 2,5-dialkylcyclohexyl,2,6-dialkylcyclohexyl, 3,4-dialkylcyclohexyl, 3-alkylcyclohexyl,4-alkylcyclohexyl, 3,3,5-trialkylcyclohexyl, cyclohexylmethyl,2-aminocyclohexyl, 3-aminocyclohexyl, 4-aminocyclohexyl,2,3-diaminocyclohexyl, 2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl,2,5-diaminocyclohexyl, 2,6-diaminocyclohexyl, 2,2-diaminocyclohexyl,2-alkoxycyclohexyl, 3-alkoxycyclohexyl, 4-alkoxycyclohexyl,2,3-dialkoxycyclohexyl, 2,4-dialkoxycyclohexyl, 3,4-dialkoxycyclohexyl,2,5-dialkoxycyclohexyl, 2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl,2-alkylthiocyclohexyl, 3-alkylthiocyclohexyl, 4-alkylthiocyclohexyl,2,3-dialkylthiocyclohexyl, 2,4-dialkylthiocyclohexyl,3,4-dialkylthiocyclohexyl, 2,5-dialkylthiocyclohexyl,2,6-dialkylthiocyclohexyl, 2,2-dialkylthiocyclohexyl, cyclopentyl,cycloheptyl, cyclohexenyl, isopropyl, n-butyl, cyclooctyl,2-arylcyclohexyl, 2-phenylcyclohexyl, 2-arylalkylcyclohexyl,2-benzylcyclohexyl, 4-phenylcyclohexyl, adamantyl, isocamphenyl,carenyl, 7,7-dialkylnorbornyl, bornyl, norbornyl, and decalinyl groups.6. The compound of claim 1, wherein R^(3′) is selected from the groupconsisting of substituted and unsubstituted cyclohexyl,2-methylcyclohexyl, 2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl,2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl,3,4-dimethylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl,cyclohexenyl, 3,3,5-trimethylcyclohexyl, 4-t-butylcyclohexyl,cyclohexylmethyl, isopinocampheyl, 7,7-dimethylnorbornyl,4-isopropylcyclohexyl, and 3-methylcycloheptyl groups.
 7. The compoundof claim 1, wherein R^(1′) is H and R^(2′) is selected from the groupconsisting of substituted and unsubstituted alkyl, arylalkyl, andheteroarylalkyl groups.
 8. The compound of claim 1, wherein R^(1′) is Hand R^(2′) is selected from the group consisting of substituted andunsubstituted dialkylaminoethyl, 4-ethylbenzyl, 3-chlorobenzyl,2,4-dichlorobenzyl, 3-methylbenzyl, benzyl, 4-fluorobenzyl,3-methoxybenzyl, 2-chlorobenzyl, and thiophene groups.
 9. The compoundof claim 1, wherein R^(1′) and R^(2′) may be the same or different andare each independently selected from the group consisting of substitutedand unsubstituted alkyl, arylalkyl, and heteroarylalkyl groups.
 10. Thecompound of claim 1, wherein R^(1′) and R^(2′) may be the same ordifferent and are each independently selected from the group consistingof substituted and unsubstituted dialkylaminoethyl, 4-ethylbenzyl,3-chlorobenzyl, 2,4-dichlorobenzyl, 3-methylbenzyl, benzyl,4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl, and thiophene groups.11. The compound of claim 1, wherein R^(1′) and R^(2′), together withthe nitrogen to which they are bound, form a substituted orunsubstituted heterocyclyl group.
 12. The compound of claim 1, whereinR^(1′) and R^(2′), together with the nitrogen to which they are bound,form a substituted or unsubstituted saturated heterocyclyl groupcomprising at least one heteroatom selected from the group consisting ofO, S, and N, in addition to the nitrogen atom to which R^(1′) and R^(2′)are bound.
 13. The compound of claim 1, wherein R^(1′) and R^(2′),together with the nitrogen to which they are bound, form a substitutedor unsubstituted piperazino, morpholino, pyrrolidino, piperidino,homopiperazino, or azepino group.
 14. The compound of claim 1, whereinR^(1′) and R^(2′), together with the nitrogen to which they are bound,form a piperazino group optionally substituted by one or two methylgroups.
 15. The compound of claim 1, wherein R^(a) is H.
 16. Thecompound of claim 1, wherein A³ is a covalent bond.
 17. The compound ofclaim 1, wherein A⁴ is a 2,4-disubstituted phenylethyl group or anindolylethyl group.
 18. The compound of claim 1, wherein A⁴ is selectedfrom the group consisting of 2,4-dihalophenylethyl, and2,4-dialkylphenylethyl groups.
 19. The compound of claim 1, wherein A⁴is selected from the group consisting of phenylethyl,2,4-dichlorophenylethyl, 4-methoxyphenylethyl, 4-bromophenylethyl,4-methylphenylethyl, 4-chlorophenylethyl, 4-ethylphenylethyl,cyclohexenylethyl, 2-methoxyphenylethyl, 2-chlorophenylethyl,2-fluorophenylethyl, 3-methoxyphenylethyl, 3-fluorophenylethyl,thienylethyl, indolylethyl, 4-hydroxyphenylethyl,3,4-dimethoxyphenylethyl, 2-chloro-4-iodophenylethyl,2-fluoro-4-methylphenylethyl, 2-fluoro-4-bromophenylethyl,2-fluoro-4-methoxyphenylethyl, 2-trifluoromethyl-4-fluorophenylethyl,2,4-difluorophenylethyl, 2,4-dimethylphenylethyl, or2,4-dimethoxyphenylethyl groups.
 20. A compound of formula I

wherein Q, W, X, Y, and Z are independently selected from the groupconsisting of carbon atoms and nitrogen atoms; R¹, R², R³, R⁴, and R⁵may be the same or different, and are each independently selected fromthe group consisting of H, Cl, I, F, Br, OH, NH₂, CN, NO₂, andsubstituted and unsubstituted aryl, alkoxy, amino, alkyl, alkenyl,alkynyl, alkylamino, dialkylamino, cycloalkyl, heterocyclylamino,heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, heteroarylaminocarbonyl groups, and groups offormula IIA or IIB;

wherein R¹ may be absent if W is a nitrogen atom; wherein R² may beabsent if X is a nitrogen atom; wherein R³ may be absent if Z is anitrogen atom; wherein R⁴ may be absent if Y is a nitrogen atom; whereinR⁵ may be absent if Q is a nitrogen atom; wherein one of R¹, R², R³, R⁴,or R⁵ is a group having the formula IIA or IIB; R^(1′) is selected fromthe group consisting of H, and substituted and unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl,heteroarylalkyl, and cycloalkylalkyl groups; R^(2′) is selected from thegroup consisting of substituted and unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl,heteroarylalkyl, and cycloalkylalkyl groups; or R^(1′) and R^(2′),together with the nitrogen to which they are bound, form a substitutedor unsubstituted heterocyclyl or heteroaryl group; R^(3′) is selectedfrom the group consisting of substituted and unsubstituted aryl, alkyl,alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl,heterocyclylalkyl, arylalkyl, heteroarylalkyl, and cycloalkylalkylgroups; R^(4′) is selected from the group consisting of H, andsubstituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclylalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl,arylalkyl, and heteroarylalkyl groups; R⁶ is a group of formula IIIA,IIIB, IIIC, IIID, or IIIE

m is an integer selected from 0, 1, or 2; n is an integer selected from0, 1, or 2; R⁷, R⁸, R⁹, and R¹⁰ may be the same or different and areindependently selected from the group consisting of H, Cl, I, F, Br, OH,NH₂, CN, NO₂, and substituted and unsubstituted alkoxy, amino, alkyl,aryl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl,heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups; R⁷ and R⁸may join together with the carbon atoms to which they are attached toform a substituted or unsubstituted 5 or 6 membered ring; R¹¹ isselected from the group consisting of H, and substituted andunsubstitued alkyl groups; R¹², R¹³, R¹⁴, and R¹⁵ may be the same ordifferent and are each independently selected from the group consistingof H, Cl, I, F, Br, OH, NH₂, CN, NO₂, and substituted and unsubstitutedalkoxy, amino, alkyl, aryl, alkenyl, alkynyl, alkylamino, dialkylamino,cycloalkyl, heterocyclylamino, heteroarylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl,arylaminocarbonyl, heterocyclylaminocarbonyl, andheteroarylaminocarbonyl groups; R¹² and R¹⁴ may represent a second bondbetween the carbon bonded to R¹² and the carbon bonded to R¹⁴ such thatthe bond between the carbon bonded to R¹² and the carbon bonded to R¹⁴is a double bond; and R¹⁶ is selected from the group consisting of H,and substituted and unsubstituted alkyl groups; R¹¹ and R¹⁶ mayrepresent a second bond between the carbon bonded to R¹⁶ and thenitrogen bonded to R¹¹ such that the bond between the carbon bonded toR¹⁶ and the nitrogen bonded to R^(1′) is a double bond; R¹⁷ is selectedfrom the group consisting of H, and substituted and unsubstitutedarylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, and alkyl groups;R¹⁸ is selected from the group consisting of H, and substituted andunsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl,alkynyl, and alkyl groups; R¹⁹ is selected from the group consisting ofsubstituted and unsubstituted arylalkyl, heteroarylalkyl, aryl,heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl,cycloalkylalkyl, alkenyl, alkynyl, and alkyl groups; and prodrugsthereof, pharmaceutically acceptable salts thereof, stereoisomersthereof, tautomers thereof, hydrates thereof, hydrides thereof, orsolvates thereof.
 21. The compound of claim 20, wherein R⁶ has theformula IIIA.
 22. The compound of claim 21, wherein m is 0 and n is 2.23. The compound of claim 21, wherein m is 1 and n is
 1. 24. Thecompound of claim 21, wherein m is 0 and n is
 1. 25. The compound ofclaim 21, wherein m is 2 and n is
 1. 26. The compound of claim 20,wherein R⁶ has the formula IIIB.
 27. The compound of claim 26, whereinR¹¹ and R¹⁶ represent a second bond between the carbon bonded to R¹⁶ andthe nitrogen bonded to R¹¹ such that the bond between the carbon bondedto R¹⁶ and the nitrogen bonded to R¹¹ is a double bond.
 28. The compoundof claim 26, wherein R¹¹ is H or a substituted or unsubstituted alkylgroup and R¹⁶ is H.
 29. The compound of claim 26, wherein at least oneof R⁸ or R⁹ is selected from the group consisting of Br, Cl, F, I,substituted and unsubstituted alkyl groups, and substituted andunsubstituted alkoxy groups.
 30. The compound of claim 20, wherein R⁶has the formula IIIC.
 31. The compound of claim 20, wherein R⁶ has theformula IIID.
 32. The compound of claim 20, wherein R⁶ has the formulaIIIE.
 33. The compound of claim 20, wherein R⁶ has the formula IIID orIIIE and R¹⁸ is H.
 34. The compound of claim 20, wherein R⁶ has theformula IIIC, IIID, or IIIE wherein R¹⁷ or R¹⁹ is selected from thegroup consisting of substituted and unsubstituted arylalkyl groups, andsubstituted and unsubstituted heteroarylalkyl groups.
 35. The compoundof claim 34, wherein R¹⁷ or R¹⁹ is a substituted or unsubstitutedphenylalkyl group or a substituted or unsubstituted indolylalkyl group.36. The compound of claim 34, wherein R¹⁷ or R¹⁹ is a 2,4-disubstitutedphenylethyl group or an indolylethyl group.
 37. The compound of claim34, wherein R¹⁷ or R¹⁹ is selected from the group consisting of2,4-dihalophenylethyl, and 2,4-dialkylphenylethyl groups.
 38. Thecompound of claim 34, wherein R¹⁷ or R¹⁹ is selected from the groupconsisting of phenylethyl, 2,4-dichlorophenylethyl,4-methoxyphenylethyl, 4-bromophenylethyl, 4-methylphenylethyl,4-chlorophenylethyl, 4-ethylphenylethyl, cyclohexenylethyl,2-methoxyphenylethyl, 2-chlorophenylethyl, 2-fluorophenylethyl,3-methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, indolylethyl,4-hydroxyphenylethyl, 3,4-dimethoxyphenylethyl,2-chloro-4-iodophenylethyl, 2-fluoro-4-methylphenylethyl,2-fluoro-4-bromophenylethyl, 2-fluoro-4-methoxyphenylethyl,2-trifluoromethyl-4-fluorophenylethyl, 2,4-difluorophenylethyl,2,4-dimethylphenylethyl, or 2,4-dimethoxyphenylethyl groups.
 39. Thecompound of claim 31, wherein R¹⁹ is a substituted arylalkyl group, andthe alkyl group of the R¹⁹ arylalkyl group is substituted with an aminoor acetamido group.
 40. The compound of claim 20, wherein Q is a carbonatom and R⁵ has the formula IIA or IIB.
 41. The compound of claim 20,wherein Q, W, X, Y, and Z are all carbon atoms.
 42. The compound ofclaim 20, wherein one of Q, W, X, Y, or Z is a nitrogen atom.
 43. Thecompound of claim 20, wherein R^(4′) is an H.
 44. The compound of claim20, wherein R^(3′) is selected from the group consisting of substitutedand unsubstituted cycloalkyl, polycyclic cycloalkyl, alkenyl, alkyl, andaryl groups.
 45. The compound of claim 20, wherein R^(3′) is selectedfrom the group consisting of substituted and unsubstituted cyclohexyl,2-alkylcyclohexyl, 2,2-dialkylcyclohexyl, 2,3-dialkylcyclohexyl,2,4-dialkylcyclohexyl, 2,5-dialkylcyclohexyl, 2,6-dialkylcyclohexyl,3,4-dialkylcyclohexyl, 3-alkylcyclohexyl, 4-alkylcyclohexyl,3,3,5-trialkylcyclohexyl, cyclohexylmethyl, 2-aminocyclohexyl,3-aminocyclohexyl, 4-aminocyclohexyl, 2,3-diaminocyclohexyl,2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl, 2,5-diaminocyclohexyl,2,6-diaminocyclohexyl, 2,2-diaminocyclohexyl, 2-alkoxycyclohexyl,3-alkoxycyclohexyl, 4-alkoxycyclohexyl, 2,3-dialkoxycyclohexyl,2,4-dialkoxycyclohexyl, 3,4-dialkoxycyclohexyl, 2,5-dialkoxycyclohexyl,2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl, 2-alkylthiocyclohexyl,3-alkylthiocyclohexyl, 4-alkylthiocyclohexyl, 2,3-dialkylthiocyclohexyl,2,4-dialkylthiocyclohexyl, 3,4-dialkylthiocyclohexyl,2,5-dialkylthiocyclohexyl, 2,6-dialkylthiocyclohexyl,2,2-dialkylthiocyclohexyl, cyclopentyl, cycloheptyl, cyclohexenyl,isopropyl, n-butyl, cyclooctyl, 2-arylcyclohexyl, 2-phenylcyclohexyl,2-arylalkylcyclohexyl, 2-benzylcyclohexyl, 4-phenylcyclohexyl,adamantyl, isocamphenyl, carenyl, 7,7-dialkylnorbornyl, bornyl,norbornyl, and decalinyl groups.
 46. The compound of of claim 20,wherein R³ is selected from the group consisting of substituted andunsubstituted cyclohexyl, 2-methylcyclohexyl, 2,2-dimethylcyclohexyl,2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl,2,6-dimethylcyclohexyl, 3,4-dimethylcyclohexyl, 3-methylcyclohexyl,4-methylcyclohexyl, cyclohexenyl, 3,3,5-trimethylcyclohexyl,4-t-butylcyclohexyl, cyclohexylmethyl, isopinocampheyl,7,7-dimethylnorbornyl, 4-isopropylcyclohexyl, and 3-methylcycloheptylgroups.
 47. The compound of claim 20, wherein R^(1′) is H and R^(2′) isselected from the group consisting of substituted and unsubstitutedalkyl, arylalkyl, and heteroarylalkyl groups.
 48. The compound of claim20, wherein R^(1′) is H and R^(2′) is selected from the group consistingof substituted and unsubstituted dialkylaminoethyl, 4-ethylbenzyl,3-chlorobenzyl, 2,4-dichlorobenzyl, 3-methylbenzyl, benzyl,4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl, and thiophene groups.49. The compound of claim 20, wherein R^(1′) and R^(2′) may be the sameor different and are each independently selected from the groupconsisting of substituted and unsubstituted alkyl, arylalkyl, andheteroarylalkyl groups.
 50. The compound of claim 20, wherein R^(1′) andR^(2′) may be the same or different and are each independently selectedfrom the group consisting of substituted and unsubstituteddialkylaminoethyl, 4-ethylbenzyl, 3-chlorobenzyl, 2,4-dichlorobenzyl,3-methylbenzyl, benzyl, 4-fluorobenzyl, 3-methoxybenzyl, 2-chlorobenzyl,and thiophene groups.
 51. The compound of claim 20, wherein R^(1′) andR^(2′) together with the nitrogen to which they are bound, form asubstituted or unsubstituted heterocyclyl group.
 52. The compound ofclaim 51, wherein R¹⁷ is H or an unsubstituted alkyl group.
 53. Thecompound of claim 52, wherein R³ is a substituted cycloalkyl group or asubstituted polycyclic cycloalkyl group.
 54. The compound of claim 20,wherein R^(1′) and R^(2′), together with the nitrogen to which they arebound, form a substituted or unsubstituted saturated heterocyclyl groupcomprising at least one heteroatom selected from the group consisting ofO, S, and N, in addition to the nitrogen atom to which R^(1′) and R^(2′)are bound.
 55. The compound of claim 54, wherein R¹⁷ is H or anunsubstituted alkyl group.
 56. The compound of claim 20, wherein R^(1′)and R^(2′), together with the nitrogen to which they are bound, form asubstituted or unsubstituted piperazino, morpholino, pyrrolidino,piperidino, homopiperazino, or azepino group.
 57. The compound of claim56, wherein R¹⁷ is H or an unsubstituted alkyl group.
 58. The compoundof claim 20, wherein R^(1′) and R^(2′), together with the nitrogen towhich they are bound, form a piperazino group optionally substituted byone or two methyl groups.
 59. A composition comprising the compoundaccording to claim 1 and a pharmaceutically acceptable carrier.
 60. Acomposition comprising the compound according to claim 20 and apharmaceutically acceptable carrier.
 61. A method of treating an MC4-Rmediated disease, comprising administering to a subject in need thereof,the compound according to claim
 1. 62. The method according to claim 61,wherein the disease is obesity or type II diabetes.
 63. A method oftreating an MC4-R mediated disease, comprising administering to asubject in need thereof, the compound according to claim
 20. 64. Themethod according to claim 63, wherein the disease is obesity or type IIdiabetes.